Picolinamide derivatives as ttx-s blockers

ABSTRACT

The present invention relates to picolinamide derivatives which have blocking activities of voltage gated sodium channels as the TTX-S channels, and which are useful in the treatment or prevention of disorders and diseases in which voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which voltage gated sodium channels are involved.

TECHNICAL FIELD

The present invention relates to picolinamide derivatives which haveblocking activities of voltage gated sodium channels as the TTX-Schannels, and which are useful in the treatment or prevention ofdisorders and diseases in which voltage gated sodium channels areinvolved. The invention also relates to pharmaceutical compositionscomprising these compounds and the use of these compounds andcompositions in the prevention or treatment of such diseases in whichvoltage gated sodium channels are involved.

BACKGROUND ART

The picolinamide derivatives of the present invention are sodium channelblockers and have a number of therapeutic applications, particularly inthe treatment of pain.

More particularly, the picolinamide derivatives of the invention areselective tetrodotoxin-sensitive (TTX-S) blockers. In the discussionthat follows, the invention is exemplified by reference to theinhibition of Na_(V1.3) and Na_(V1.7) channels as the TTX-S channels.They show the affinity for both Na_(V1.3) and Na_(V1.7) channels whichis significantly greater than their affinity for Na_(V1.5) channel asthe tetrodotoxin-resistant (TTX-R) sodium channels. Preferredpicolinamide derivatives of the invention show at least a 10-foldselectivity for the Na_(V1.3) and Na_(V1.7) channels as compared withNa_(V1.5) channel.

The rat Na_(V1.3) channel and the human Na_(V1.3) channel have beencloned in 1988 and 1998/2000 respectively (FEBS Lett. 228 (1), 187-194,1988; J. Mol. Neurosci., 10 (1), 67-70, 1998; Eur. J. Neurosci. 12 (12),4281-4289, 2000). The Na_(V1.3) channel was formerly known as brain typeIII sodium channel. Na_(V1.3) is present at relatively high levels inthe nervous system of rat embryos but is barely detectable in adultrats. Na_(V1.3) is up-regulated following axotomy in the Spinal NerveLigation (SNL), Chronic Constriction Injury (CCI), and diabeticneuropathy models (J Neurophysiol 82, 2776-2785, 1999. J. A. Black etal.; Ann Neurol 52, 786-792, 2002. M. J. Cranner et al.; Pain 83,591-600, 1999. S. Dib-Hajj et al.; J Biol Chem 279, 29341-29350, 2004.S. Hong et al.; Mol Brain Res 95, 153-161, 2001. C. H. Kim et al.) Theup-regulation of Na_(V1.3) channel contributes to rapidly reprimingsodium current in small dorsal root ganglion (DRG) neurons (JNeurophysiol 82, 2776-2785, 1999. J. A. Black et al.). Theseobservations suggest that Na_(V1.3) may make a key contribution toneuronal hyperexcitability.

In order to validate the contribution of Na_(V1.3) sodium channel in thepain states, specific antisense oligonucleotides (ASO) were used inanimal pain models. Na_(V1.3) sodium channel ASO treatment significantlyattenuated pain-related behaviors after CCI operation (J. Neurosci. 24,4832-4839, 2004, Hains, B. C. et al.). These finding suggest thatNa_(V1.3) sodium channel blocker is useful to treat neuropathic painconditions.

The Na_(V1.7) channel appears to be the best ‘validated’ pain target.The most exciting findings with respect to Na_(V1.7) have come fromhuman genetic studies. Cox et al. (Nature 444, 894-898, 2006) discoveredSCN9A mutations that cause a loss of Na_(V1.7) function in threefamilies from Pakistan. Their observations link loss of Na_(V1.7)function with a congenital inability to experience pain, adding to theevidence indicating Na_(V1.7) channel as an essential participant inhuman nociception.

By contrast, Gain-of-function mutations have also been described thatlead to enhanced pain, for example, Primary Erythermalgia in one caseand Paroxysmal Extreme Pain Disorder in another. These gain-of-functionmutations in patients led to different types of gating changes inNa_(V1.7) sodium currents and, interestingly, different degrees ofeffectiveness of specific sodium channel blocking drugs. The implicationfrom these findings is that a selective Na_(V1.7) blocker may be aneffective treatment for pain in man.

A local anaesthetic lidocaine and a volatile anaesthetic halothane areknown to act on both TTX-R and TTX-S sodium channels with poorselectivity and low potency (IC₅₀ values range from 50 microM to 10 mM).These anaesthetics at high systemic concentrations could causedevastating side effects, e.g., paralysis and cardiac arrest. However,systemic administration of lidocaine at low concentrations is effectiveto treat chronic pain (Trends in Pharm. Sci 22, 27-31, 2001, Baker, M.D. et al.). In rats, application of a very low dose of TTX to the DRG ofthe injured segment of the L5 spinal nerve significantly reducesmechanical allodynic behavior (Brain Res 871, 98-103, 2000, Lyu, Y. S.et al.). This suggests that TTX-S subtypes of sodium channels play animportant role in maintaining allodynic behaviors in an animal model ofneuropathic pain.

The Na_(V1.5) channel is also a member of TTX-resistant sodium channels.The Na_(V1.5) channel is almost exclusively expressed in cardiac tissueand has been shown to underlie a variety of cardiac arrhythmias andconduction disorders.

SUMMARY OF INVENTION Technical Problem

It is an objective of the invention to provide new TTX-S blockers thatare good drug candidates. Preferred compounds should bind potently tothe TTX-S (Na_(V1.3) and Na_(V1.7)) channels whilst showing littleaffinity for other sodium channels, particularly the Na_(V1.5) channel.They should be well absorbed from the gastrointestinal tract, bemetabolically stable and possess favorable pharmacokinetic properties.They should be non-toxic and demonstrate few side-effects. Furthermore,the ideal drug candidate will exist in a physical form that is stable,non-hygroscopic and easily formulated.

In particular, the picolinamide derivatives of the present invention areselective for the TTX-S channels over the Na_(V1.5) channel, leading toimprovements in the side-effect profile.

The picolinamide derivatives of the present invention are thereforeuseful in the treatment of a wide range of disorders, particularly pain,acute pain, chronic pain, neuropathic pain, inflammatory pain, visceralpain, nociceptive pain including post-surgical pain, and mixed paintypes involving the viscera, gastrointestinal tract, cranial structures,musculoskeletal system, spine, urogenital system, cardiovascular systemand CNS, including cancer pain, back and orofacial pain.

Other conditions that may be treated with the picolinamide derivativesof the present invention include multiple sclerosis, neurodegenerativedisorders, irritable bowel syndrome, osteoarthritis, rheumatoidarthritis, neuropathological disorders, functional bowel disorders,inflammatory bowel diseases, pain associated with dysmenorrhea, pelvicpain, cystitis, pancreatitis, migraine, cluster and tension headaches,diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgiaCrohn's disease, epilepsy or epileptic conditions, bipolar depression,tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorderssuch as anxiety and depression, myotonia, arrhythmia, movementdisorders, neuroendocrine disorders, ataxia, incontinence, visceralpain, trigeminal neuralgia, herpetic neuralgia, general neuralgia,postherpetic neuralgia, radicular pain, sciatica, back pain, head orneck pain, severe or intractable pain, breakthrough pain, postsurgicalpain, stroke, cancer pain, seizure disorder and causalgia.

Structurally close compounds are disclosed in WO 2007/085565. However,the patent only disclosed halogen or alkyl group and never mentioned theamide group as a substituent at the 2-position on the pyridine ring,which is quite different from the compounds of this invention. Inaddition the compounds in WO 2007/085565 are useful for the combatingpests, whereas the compounds of this invention are useful for thetreatment of a condition or disorder mediated by TTX-S channel describedin the former paragraph.

Solution to Problem

The present invention is directed to picolinamide derivatives compoundswhich are TTX-S blockers over the Na_(V1.5) channel, and which areuseful in the treatment or prevention of neurological and psychiatricdisorders and diseases in which TTX-S channels are involved. Theinvention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which TTX-S sodium channelsare involved.

The present invention provides compounds of formula (I) and saltsthereof:

wherein:

R¹ is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) hydroxy, (4) —O_(p)—C₁₋₆ alkyl, where thealkyl is unsubstituted or substituted with one or more substituentsselected from R⁵, (5) —O_(p)—C₃₋₈ cycloalkyl, where the cycloalkyl isunsubstituted or substituted with one or more substituents selected fromR⁵, (6) C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substitutedwith one or more substituents selected from R⁵, (7) —(C═O)—NR⁶R⁷, (8)—NR⁶R⁷, (9) —S(O)₂—NR⁶R⁷, (10) —NR⁶—S(O)₂R⁷, (11) —S(O)_(r)—R⁸, where ris 0, 1 or 2 and where R⁸ is selected from the definitions of R⁶ and R⁷,(12) —CO₂H, and (13) —CN; where p is 0 or 1 (wherein if p is 0, achemical bond is present in the place of O_(p));

n is 1, 2, or 3; when n is two or more than two, R¹ may be same ordifferent;

R² is selected from the group consisting of:

(1) hydrogen, (2) C₁₋₆ alkyl, which is unsubstituted or substituted withone or more substituents selected from R⁵, (3) C₃₋₈ cycloalkyl which isunsubstituted or substituted with one or more substituents selected fromR⁵, (4) phenyl, which is unsubstituted or substituted with one or moresubstituents selected from R⁵, and (5) heterocycle, which isunsubstituted or substituted with one or more substituents selected fromR⁵;

R³ is selected from the group consisting of:

(1) —C₀₋₃ alkyl-O_(p)—C₀₋₃ alkyl-cycloalkyl which is unsubstituted orsubstituted with one or more substituents selected from R⁵, (2) —C₀₋₃alkyl-O_(p)—C₀₋₃ alkyl-phenyl, which is unsubstituted or substitutedwith one or more substituents selected from R⁵, and (3) —C₀₋₃alkyl-O_(p)—C₀₋₃ alkyl-heterocycle, which is unsubstituted orsubstituted with one or more substituents selected from R⁵; where p is 0or 1, (wherein if p is 0, a chemical bond is present in the place ofO_(p));

R⁴ is selected from the group consisting of:

(1) hydrogen, (2) C₁₋₆ alkyl, and (3) hydroxy;

m is 1, 2, or 3; when m is two or more than two, R⁴ may be same ordifferent; R⁴ may form the bond with any of carbon atom on the cyclicamine ring;

k is 0 or 1;

Y is oxygen atom or carbon atom;

R⁵ is selected from the group consisting of:

(1) halogen, (2) hydroxy, (3) —(C═O)_(q)—O_(r)—C₁₋₆ alkyl, where thealkyl is unsubstituted or substituted with one or more substituentsselected from R⁹, (4) —O_(p)—(C₁₋₃) perfluoroalkyl, (5)—(C═O)_(q)—O_(r)—C₃₋₈ cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R⁹, (6)—(C═O)_(q)—O, C₂₋₄ alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R⁹, (7)—(C═O)_(q)—O_(r)-phenyl or —(C═O)_(q)—O_(r)-napthyl, where the phenyl ornapthyl is unsubstituted or substituted with one or more substituentsselected from R⁹, (8) —(C═O)_(q)—O, heterocycle, where the heterocycleis unsubstituted or substituted with one or more substituents selectedfrom R⁹, (9) —(C═O)—NR⁶R⁷, (10) —NR⁶R⁷, (11) —S(O)₂—NR⁶R⁷, (12)—S(O)—R⁸, where t is 0, 1 or 2, (13) —CO₂H, (14) —CN, and (15) —NO₂;where p is 0 or 1, (wherein if p is 0, a chemical bond is present in theplace of O_(p)) and where q is 0 or 1 and r is 0 or 1 (wherein if q is 0or r is 0, a bond is present in the place of (C═O)_(q) or O_(r), andwherein if q is 0 and r is 0, a single bond is present in the place of(C═O)_(q)—O_(r));

R⁶ and R⁷ are independently selected from the group consisting of:

(1) hydrogen, (2) C₁₋₆ alkyl, which is unsubstituted or substituted withR⁵, (3) C₃₋₆ alkenyl, which is unsubstituted or substituted with R⁵, (4)C₃₋₈ cycloalkyl which is unsubstituted or substituted with R⁵, (5)phenyl, which is unsubstituted or substituted with R⁵, and (6)heterocycle, which is unsubstituted or substituted with R⁵, or R⁶ and R⁷taken together with the nitrogen atom to which they are attached form a3 to 8 membered ring, where the ring may contain one to four heteroatomindependently selected from nitrogen, oxygen, and sulfur; where the ringmay be saturated or partially saturated or unsaturated; which isunsubstituted or substituted one or more substituents selected from R⁵;

R⁸ is selected from the definitions of R⁶ and R⁷;

R⁹ is selected from the group consisting of:

(1) hydroxy, (2) halogen, (3) C₁₋₆ alkyl, (4) —C₃₋₈ cycloalkyl, (5)—O—C₁₋₆ alkyl, (6) —O(C═O)—C₁₋₆ alkyl, (7) —NH—C₁₋₆ alkyl, (8) phenyl,(9) heterocycle, (10) —CO₂H, and (11) —CN;

or a pharmaceutically acceptable salt thereof.

The present invention also provides compounds of formula (I-1) and saltsthereof:

wherein:

R¹ is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) hydroxy, (4) —O_(p)—C₁₋₆ alkyl, where thealkyl is unsubstituted or substituted with one or more substituentsselected from R⁵, (5) —O_(p)—C₃₋₈ cycloalkyl, where the cycloalkyl isunsubstituted or substituted with one or more substituents selected fromR⁵, (6) C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substitutedwith one or more substituents selected from R⁵, (7) —(C═O)—NR⁶R⁷, (8)—NR⁶R⁷, (9) —S(O)₂—NR⁶R⁷, (10) —NR⁶—S(O)₂R⁷, (11) —S(O)_(r)—R⁸, where ris 0, 1 or 2 and where R⁸ is selected from the definitions of R⁶ and R⁷,(12) —CO₂H, and (13) —CN; where p is 0 or 1 (wherein if p is 0, achemical bond is present in the place of O_(p));

n is 1, 2, or 3; when n is two or more than two, R¹ may be same ordifferent;

R² is selected from the group consisting of:

(1) hydrogen, (2) C₁₋₆ alkyl, which is unsubstituted or substituted withone or more substituents selected from R⁵, (3) C₃₋₈ cycloalkyl which isunsubstituted or substituted with one or more substituents selected fromR⁵, (4) phenyl, which is unsubstituted or substituted with one or moresubstituents selected from R⁵, and (5) heterocycle, which isunsubstituted or substituted with one or more substituents selected fromR⁵;

R³ is selected from the group consisting of:

(1) —C₀₋₃ alkyl-O_(p)—C₀₋₃ alkyl-cycloalkyl which is unsubstituted orsubstituted with one or more substituents selected from R⁵, (2) —C₀₋₃alkyl-O_(p)—C₀₋₃ alkyl-phenyl, which is unsubstituted or substitutedwith one or more substituents selected from R⁵, and (3) —C₀₋₃alkyl-O_(p)—C₀₋₃ alkyl-heterocycle, which is unsubstituted orsubstituted with one or more substituents selected from R⁵; where p is 0or 1, (wherein if p is 0, a chemical bond is present in the place ofO_(p));

R⁴ is selected from the group consisting of:

(1) hydrogen, and (2) hydroxy;

R⁵ is selected from the group consisting of:

(1) halogen, (2) hydroxy, (3) —(C═O)_(q)—O_(r)—C₁₋₆ alkyl, where thealkyl is unsubstituted or substituted with one or more substituentsselected from R⁹, (4) —O_(p)—(C₁₋₃)perfluoroalkyl, (5)—(C═O)_(q)—O_(r)—C₃₋₈ cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R⁹, (6)—(C═O)_(q)—O, C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R⁹, (7)—(C═O)_(q)—O, phenyl or —(C═O)_(q)—O_(r)-napthyl, where the phenyl ornapthyl is unsubstituted or substituted with one or more substituentsselected from R⁹, (8) —(C═O)_(q)—O_(r)-heterocycle where the heterocycleis unsubstituted or substituted with one or more substituents selectedfrom R⁹, (9) —(C═O)—NR⁶R⁷, (10) —NR⁶R⁷, (11) —S(O)₂—NR⁶R⁷, (12)—S(O)_(t)—R⁸, where t is 0, 1 or 2, (13) —CO₂H, (14) —CN, and (15) —NO₂;where p is 0 or 1, (wherein if p is 0, a chemical bond is present in theplace of O_(p)) and where q is 0 or 1 and r is 0 or 1 (wherein if q is 0or r is 0, a bond is present in the place of (C═O)_(q) or O_(r), andwherein if q is 0 and r is 0, a single bond is present in the place of(C═O)_(q)—O_(r));

R⁶ and R⁷ are independently selected from the group consisting of:

(1) hydrogen, (2) C₁₋₆ alkyl, which is unsubstituted or substituted withR⁵, (3) C₃₋₆ alkenyl, which is unsubstituted or substituted with R⁵, (4)C₃₋₈ cycloalkyl which is unsubstituted or substituted with R⁵, (5)phenyl, which is unsubstituted or substituted with R⁵, and (6)heterocycle, which is unsubstituted or substituted with R⁵, or R⁶ and R⁷taken together with the nitrogen atom to which they are attached form a3 to 8 membered ring, where the ring may contain one to four heteroatomindependently selected from nitrogen, oxygen, and sulfur; where the ringmay be saturated or partially saturated or unsaturated; which isunsubstituted or substituted one or more substituents selected from R⁵;

R⁸ is selected from the definitions of R⁶ and R⁷;

R⁹ is selected from the group consisting of:

(1) hydroxy, (2) halogen, (3) C₁₋₆ alkyl, (4) —C₃₋₈ cycloalkyl, (5)—O—C₁₋₆ alkyl, (6) —O(C═O)—C₁₋₆ alkyl, (7) —NH—C₁₋₆ alkyl, (8) phenyl,(9) heterocycle, (10) —CO₂H, and (11) —CN;

or a pharmaceutically acceptable salt thereof.

Preferable compounds of this invention are in formula (I) and (1-1)wherein the definition described above:

R¹ is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) hydroxy, (4) —O_(p)—C₁₋₆ alkyl, where thealkyl is unsubstituted or substituted with one or more substituentsselected from R⁵, and (5) —O_(p)—C₃₋₈ cycloalkyl, where the cycloalkylis unsubstituted or substituted with one or more substituents selectedfrom R⁵; where p is 0 or 1 (wherein if p is 0, a chemical bond ispresent in the place of O_(p));

n is 1, 2, or 3; when n is two or more than two, R¹ may be same ordifferent;

R³ is 3 to 8 membered ring where the ring may contain one to fourheteroatom independently selected from nitrogen, oxygen, and sulfur;where the ring may be saturated or unsaturated; and where the ring isoptionally substituted with 1 to 4 substituents independently selectedfrom the group consisting of:

(1) hydroxy, (2) halogen, (3) C₁₋₆ alkyl, which is unsubstituted orsubstituted with one or more substituents selected from R⁵, (4) C₃₋₈cycloalkyl, which is unsubstituted or substituted with one or moresubstituents selected from R⁵, (5) —O—C₁₋₆ alkyl, which is unsubstitutedor substituted with one or more substituents selected from R⁵, and (6)—O—C₃₋₈ cycloalkyl, which is unsubstituted or substituted with one ormore substituents selected from R⁵;

R⁵ is selected from the group consisting of:

(1) halogen, (2) hydroxy, (3) —(C═O)_(q)—O_(r)—C₁₋₆ alkyl, where thealkyl is unsubstituted or substituted with one or more substituentsselected from R⁹, (4) —O_(p)—(C₁₋₃) perfluoroalkyl, (5)—(C═O)_(q)—O_(r)—C₃₋₈ cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R⁹, (6)—(C═O)_(q)—O_(r)-phenyl, where the phenyl is unsubstituted orsubstituted with one or more substituents selected from R⁹, (7)—(C═O)_(q)—O_(r)-heterocycle, where the heterocycle is unsubstituted orsubstituted with one or more substituents selected from R⁹, (8)—(C═O)—NR⁶R⁷, (9) —NR⁶R⁷, (10) —S(O)₂—NR⁶R⁷, and (11) —S(O)—R⁸, where tis 0, 1 or 2; where p is 0 or 1, (wherein if p is 0, a chemical bond ispresent in the place of O_(p)) and where q is 0 or 1 and r is 0 or 1(wherein if q is 0 or r is 0, a bond is present in the place of(C═O)_(q) or O_(r), and wherein if q is 0 and r is 0, a single bond ispresent in the place of (C═O)_(q)—O_(r));

R⁹ is selected from the group consisting of:

(1) hydroxy, (2) halogen, (3) C₁₋₆ alkyl, (4) —C₃₋₈ cycloalkyl, (5)—O—C₁₋₆ alkyl, (6) —O(C═O)—C₁₋₆ alkyl, (7) —NH—C₁₋₆ alkyl, (8) phenyl,and (9) heterocycle;

or a pharmaceutically acceptable salt thereof.

The more preferable compounds are selected from:

-   3-(((S)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)-3-((1-(4-(trifluoromethoxy)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)-3-((1-(4-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)-3-((1-(3-chloro-2-fluorobenzoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)-3-((1-(2-(4-(trifluoromethyl)phenyl)acetyl)pyrrolidin-2-yl)methoxy)picolinamide-   (R)-3-((1-(2-(4-(trifluoromethyl)phenyl)acetyl)pyrrolidin-2-yl)methoxy)picolinamide-   (R)-3-((1-(6-tert-butylnicotinoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)-3-((1-(5-tert-butylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)-3-((1-(5-tert-butylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)-3-((1-(2-(4-(trifluoromethyl)phenoxy)acetyl)pyrrolidin-2-yl)methoxy)picolinamide-   (R)-3-((1-(4-(2,2,2-trifluoroethoxy)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   5-chloro-3-(((R)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   5-chloro-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m    ethoxy)picolinamide,-   5-(trifluoromethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(2-hydroxyethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidi    n-2-yl)methoxy)picolinamide,-   (R)—N-(2-methoxyethyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)—N-((1-hydroxycyclohexyl)methyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   Methyl    2-(3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamido)acetate,-   N-(2-methoxyethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-((1-hydroxycyclohexyl)methyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(pyridin-2-ylmethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-benzyl-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-phenyl-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(pyridin-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(4H-1,2,4-triazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N—((R)-2-hydroxy-1-phenylethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(oxazol-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexane    carbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(tetrahydro-2H-pyran-4-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(5-methylisoxazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(1-methyl-1H-pyrazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(isoxazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(oxazol-2-yl)-3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)-3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide,-   N-(pyrazin-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   N-(isoxazol-5-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)—N-(pyridin-2-ylmethyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   (R)—N-benzyl-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide-   (R)—N-(pyridin-2-yl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,-   3-(((2R,4R)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide,-   5-chloro-3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide,-   5-chloro-3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hex    an-1-yl)methoxy)picolinamide,-   3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)picolinamide,-   N-((tetrahydro-2H-pyran-4-yl)methyl)-3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide,-   N-(tetrahydro-2H-pyran-4-yl)-3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide,-   N-((tetrahydro-2H-pyran-4-yl)methyl)-3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide    and-   N-(tetrahydro-2H-pyran-4-yl)-3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide.

Also, the present invention provides the use of a compound of formula(I) or a pharmaceutically acceptable salt thereof, each as describedherein, for the manufacture of a medicament for the treatment of acondition or disorder mediated by TTX-S channel; in particular,Na_(V1.3) channels blocking activity. In order to use the compounds offormula (I) and pharmaceutically acceptable salts thereof in therapy,they will normally be formulated into a pharmaceutical composition inaccordance with standard pharmaceutical practice. The present inventionalso provides a pharmaceutical composition, which comprises a compoundof formula (I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or excipient.

Preferably, the present invention also provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, each asdescribed herein, for the manufacture of a medicament for the treatmentof diseases selected from TTX-S channels related diseases.

Also, the present invention provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof, each as described herein, together with a pharmaceuticallyacceptable carrier for said compound.

Also, the present invention provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof, each as described herein, together with a pharmaceuticallyacceptable carrier for said compound and another pharmacologicallyactive agent.

Also, the present invention provides a process for preparing apharmaceutical composition, the process comprising mixing a compound offormula (I) or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or excipient.

Also, the present invention provides an intermediate in a process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

Further, the present invention provides a method of treatment of acondition or disorder mediated by TTX-S channels blocking activity, in amammalian subject, which comprises administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, each asdescribed herein.

In a further aspect, the present invention provides a process forpreparing a pharmaceutical composition, the process comprising mixing acompound of formula (I) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier or excipient.

ADVANTAGEOUS EFFECTS OF INVENTION

Examples of conditions or disorders mediated by TTX-S channels blockingactivity include, but are not limited to, TTX-S channels relateddiseases. The compounds of the present invention show the TTX-S channelsblocking activity. The compounds of the present invention may show lesstoxicity, good absorption, distribution, good solubility, less proteinbinding affinity other than TTX-S channels, less drug-drug interaction,and good metabolic stability.

DESCRIPTION OF EMBODIMENTS

As appreciated by those of skill in the art, “halogen” or “halo” as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆ alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₆ alkyl specifically includes methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. Similarly,C₂₋₆ alkenyl is defined to identify the group as having 2, 3, 4, 5 or 6carbons which incorporates at least one double bond, which may be in aE- or a Z-arrangement. A group which is designated as beingindependently substituted with substituents may be independentlysubstituted with multiple numbers of such substituents.

The term “alkenyl”, as used herein, means a hydrocarbon radical havingat least one double bond including, but not limited to, ethenyl,propenyl, 1-butenyl, 2-butenyl and the like.

The term “cycloalkyl”, as used herein, means a mono- or bicyclic ring,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, norboranyl, and adamantyl groups and the like.

The term “heterocycle” as used herein includes both unsaturated andsaturated heterocyclic moieties, wherein the unsaturated heterocyclicmoieties include benzoimidazolyl, benzimidazolonyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazolinyl, isoxazolinyl, oxetanyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, andN-oxides thereof, and wherein the saturated heterocyclic moietiesinclude azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl,tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxidesthereof and S-oxides thereof.

The term “C₀”, as used herein, means direct bond.

The term “treating” and “treatment”, as used herein, refers to curative,palliative and prophylactic treatment, including reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition.

As used herein, the article “a” or “an” refers to both the singular andplural form of the object to which it refers unless indicated otherwise.

Included within the scope of the “compounds of the invention” are allsalts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeledderivatives, stereoisomers and optical isomers of the compounds offormula (I).

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. ScL, 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, formic, acetic, trifluoroacetic,propionic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic,methanesulfonic or naphthalenesulfonic acid. Certain of the compounds offormula (I) may form acid addition salts with one or more equivalents ofthe acid. The present invention includes within its scope all possiblestoichiometric and non-stoichiometric forms. In addition, certaincompounds containing an acidic function such as a carboxy can beisolated in the form of their inorganic salt in which the counter ioncan be selected from sodium, potassium, lithium, calcium, magnesium andthe like, as well as from organic bases.

The compounds of formula (I) and salts thereof may be prepared incrystalline or non-crystalline form, and, if crystalline, may optionallybe hydrated or solvated. This invention includes within its scopestoichiometric hydrates or solvates as well as compounds containingvariable amounts of water and/or solvent.

Salts and solvates having non-pharmaceutically acceptable counter-ionsor associated solvents are within the scope of the present invention,for example, for use as intermediates in the preparation of othercompounds of formula (I) and their pharmaceutically acceptable salts.

The compounds of formula (I) may have polymorphs in crystalline form,which are within the scope of the present invention.

Additionally, the compounds of formula (I) may be administered asprodrugs. As used herein, a “prodrug” of a compound of formula (I) is afunctional derivative of the compound which, upon administration to apatient, eventually liberates the compound of formula (I) in vivo.Administration of a compound of formula (I) as a prodrug may enable theskilled artisan to do one or more of the following: (a) modify the onsetof action of the compound in vivo; (b) modify the duration of action ofthe compound in vivo; (c) modify the transportation or distribution ofthe compound in vivo; (d) modify the solubility of the compound in vivo;and (e) overcome a side effect or other difficulty encountered with thecompound. Typical functional derivatives used to prepare prodrugsinclude modifications of the compound that are chemically orenzymatically cleaved in vivo. Such modifications, which include thepreparation of phosphates, amides, esters, thioesters, carbonates, andcarbamates, are well known to those skilled in the art.

In certain of the compounds of formula (I), there may be some chiralcarbon atoms. In such cases, compounds of formula (I) exist asstereoisomers. The invention extends to all optical isomers such asstereoisomeric forms of the compounds of formula (I) includingenantiomers, diastereoisomers and mixtures thereof, such as racemates.The different stereoisomeric forms may be separated or resolved one fromthe other by conventional methods or any given isomer may be obtained byconventional stereoselective or asymmetric syntheses.

Certain of the compounds herein can exist in various tautomeric formsand it is to be understood that the invention encompasses all suchtautomeric forms.

The invention also includes isotopically-labeled compounds, which areidentical to those described herein, but for the fact that one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, iodine, and chlorine, such as ³H, ¹¹C, ¹⁴C, ¹⁸F,¹²³I and ¹²⁵I. Compounds of the invention that contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of the present invention. Isotopically-labeled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H, ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. ¹¹C and ¹⁸F isotopes are particularly useful in PET(positron emission tomography), and ¹²⁵I isotopes are particularlyuseful in SPECT (single photon emission computerized tomography), alluseful in brain imaging. Further, substitution with heavier isotopessuch as deuterium, i.e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances, Isotopically labeled compounds of theinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, then substitutinga readily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

With respect to other compounds disclosed in the art, the presentcompounds exhibit unexpected properties, such as with respect toduration of action and/or metabolism, such as increased metabolicstability, enhanced oral bioavailability or absorption, and/or decreaseddrug-drug interactions.

The compounds of formula (I), being Na_(V1.3) channel blockers, arepotentially useful in the treatment of a range of disorders. Thetreatment of pain, particularly chronic, inflammatory, neuropathic,nociceptive and visceral pain, is a preferred use.

Physiological pain is an important protective mechanism designed to warnof danger from potentially injurious stimuli from the externalenvironment. The system operates through a specific set of primarysensory neurones and is activated by noxious stimuli via peripheraltransducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164for a review). These sensory fibres are known as nociceptors and arecharacteristically small diameter axons with slow conduction velocities.Nociceptors encode the intensity, duration and quality of noxiousstimulus and by virtue of their topographically organised projection tothe spinal cord, the location of the stimulus. The nociceptors are foundon nociceptive nerve fibres of which there are two main types, A-deltafibres (myelinated) and C fibres (non-myelinated). The activitygenerated by nociceptor input is transferred, after complex processingin the dorsal horn, either directly, or via brain stem relay nuclei, tothe ventrobasal thalamus and then on to the cortex, where the sensationof pain is generated.

Pain may generally be classified as acute or chronic. Acute pain beginssuddenly and is short-lived (usually in twelve weeks or less). It isusually associated with a specific cause such as a specific injury andis often sharp and severe. It is the kind of pain that can occur afterspecific injuries resulting from surgery, dental work, a strain or asprain. Acute pain does not generally result in any persistentpsychological response. In contrast, chronic pain is long-term pain,typically persisting for more than three months and leading tosignificant psychological and emotional problems. Common examples ofchronic pain are neuropathic pain (e.g. painful diabetic neuropathy,postherpetic neuralgia), carpal tunnel syndrome, back pain, headache,cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma,the characteristics of nociceptor activation are altered and there issensitisation in the periphery, locally around the injury and centrallywhere the nociceptors terminate. These effects lead to a heightenedsensation of pain. In acute pain these mechanisms can be useful, inpromoting protective behaviours which may better enable repair processesto take place. The normal expectation would be that sensitivity returnsto normal once the injury has healed. However, in many chronic painstates, the hypersensitivity far outlasts the healing process and isoften due to nervous system injury. This injury often leads toabnormalities in sensory nerve fibres associated with maladaptation andaberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivityfeature among the patient's symptoms. Patients tend to be quiteheterogeneous and may present with various pain symptoms. Such symptomsinclude: 1) spontaneous pain which may be dull, burning, or stabbing; 2)exaggerated pain responses to noxious stimuli (hyperalgesia); and 3)pain produced by normally innocuous stimuli (allodynia—Meyer et al.,1994, Textbook of Pain, 13-44). Although patients suffering from variousforms of acute and chronic pain may have similar symptoms, theunderlying mechanisms may be different and may, therefore, requiredifferent treatment strategies. Pain can also therefore be divided intoa number of different subtypes according to differing pathophysiology,including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli withthe potential to cause injury. Pain afferents are activated bytransduction of stimuli by nociceptors at the site of injury andactivate neurons in the spinal cord at the level of their termination.This is then relayed up the spinal tracts to the brain where pain isperceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activationof nociceptors activates two types of afferent nerve fibres. MyelinatedA-delta fibres transmit rapidly and are responsible for sharp andstabbing pain sensations, whilst unmyelinated C fibres transmit at aslower rate and convey a dull or aching pain. Moderate to severe acutenociceptive pain is a prominent feature of pain from central nervoussystem trauma, strains/sprains, burns, myocardial infarction and acutepancreatitis, post-operative pain (pain following any type of surgicalprocedure), posttraumatic pain, renal colic, cancer pain and back pain.Cancer pain may be chronic pain such as tumour related pain (e.g. bonepain, headache, facial pain or visceral pain) or pain associated withcancer therapy (e.g. postchemotherapy syndrome, chronic postsurgicalpain syndrome or post radiation syndrome). Cancer pain may also occur inresponse to chemotherapy, immunotherapy, hormonal therapy orradiotherapy. Back pain may be due to herniated or rupturedintervertebral discs or abnormalities of the lumber facet joints,sacroiliac joints, paraspinal muscles or the posterior longitudinalligament. Back pain may resolve naturally but in some patients, where itlasts over 12 weeks, it becomes a chronic condition which can beparticularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by aprimary lesion or dysfunction in the nervous system. Nerve damage can becaused by trauma and disease and thus the term ‘neuropathic pain’encompasses many disorders with diverse aetiologies. These include, butare not limited to, peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy,HIV neuropathy, phantom limb pain, carpal tunnel syndrome, centralpost-stroke pain and pain associated with chronic alcoholism,hypothyroidism, uremia, multiple sclerosis, spinal cord injury,Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic painis pathological as it has no protective role. It is often present wellafter the original cause has dissipated, commonly lasting for years,significantly decreasing a patient's quality of life (Woolf and Mannion,1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain aredifficult to treat, as they are often heterogeneous even betweenpatients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6,S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Theyinclude spontaneous pain, which can be continuous, and paroxysmal orabnormal evoked pain, such as hyperalgesia (increased sensitivity to anoxious stimulus) and allodynia (sensitivity to a normally innocuousstimulus).

The inflammatory process is a complex series of biochemical and cellularevents, activated in response to tissue injury or the presence offoreign substances, which results in swelling and pain (Levine andTaiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most commoninflammatory pain. Rheumatoid disease is one of the commonest chronicinflammatory conditions in developed countries and rheumatoid arthritisis a common cause of disability. The exact aetiology of rheumatoidarthritis is unknown, but current hypotheses suggest that both geneticand microbiological factors may be important (Grennan & Jayson, 1994,Textbook of Pain, 397-407). It has been estimated that almost 16 millionAmericans have symptomatic osteoarthritis (OA) or degenerative jointdisease, most of whom are over 60 years of age, and this is expected toincrease to 40 million as the age of the population increases, makingthis a public health problem of enormous magnitude (Houge & Mersfelder,2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook ofPain, 387-395). Most patients with osteoarthritis seek medical attentionbecause of the associated pain. Arthritis has a significant impact onpsychosocial and physical function and is known to be the leading causeof disability in later life. Ankylosing spondylitis is also a rheumaticdisease that causes arthritis of the spine and sacroiliac joints. Itvaries from intermittent episodes of back pain that occur throughoutlife to a severe chronic disease that attacks the spine, peripheraljoints and other body organs.

Another type of inflammatory pain is visceral pain which includes painassociated with inflammatory bowel disease (IBD). Visceral pain is painassociated with the viscera, which encompass the organs of the abdominalcavity. These organs include the sex organs, spleen and part of thedigestive system. Pain associated with the viscera can be divided intodigestive visceral pain and non-digestive visceral pain. Commonlyencountered gastrointestinal (GI) disorders that cause pain includefunctional bowel disorder (FBD) and inflammatory bowel disease (IBD).These GI disorders include a wide range of disease states that arecurrently only moderately controlled, including, in respect of FBD,gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) andfunctional abdominal pain syndrome (FAPS), and, in respect of IBD,Crohn's disease, ileitis and ulcerative colitis, all of which regularlyproduce visceral pain. Other types of visceral pain include the painassociated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies andthus can be classified in more than one area, e.g. back pain and cancerpain have both nociceptive and neuropathic components.

Other types of pain include:

-   -   pain resulting from musculo-skeletal disorders, including        myalgia, fibromyalgia, spondylitis, sero-negative        (non-rheumatoid) arthropathies, non-articular rheumatism,        dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;    -   heart and vascular pain, including pain caused by angina,        myocardical infarction, mitral stenosis, pericarditis, Raynaud's        phenomenon, scleredoma and skeletal muscle ischemia;    -   head pain, such as migraine (including migraine with aura and        migraine without aura), cluster headache, tension-type headache        mixed headache and headache associated with vascular disorders;        and    -   orofacial pain, including dental pain, otic pain, burning mouth        syndrome and temporomandibular myofascial pain.

The picolinamide derivatives of formula (I) are also expected to beuseful in the treatment of multiple sclerosis.

The invention also relates to therapeutic use of the picolinamidederivatives of formula (I) as agents for treating or relieving thesymptoms of neurodegenerative disorders. Such neurodegenerativedisorders include, for example, Alzheimer's disease, Huntington'sdisease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Thepresent invention also covers treating neurodegenerative disorderstermed acute brain injury. These include but are not limited to: stroke,head trauma, and asphyxia. Stroke refers to a cerebral vascular diseaseand may also be referred to as a cerebral vascular accident (CVA) andincludes acute thromboembolic stroke. Stroke includes both focal andglobal ischemia. Also, included are transient cerebral ischemic attacksand other cerebral vascular problems accompanied by cerebral ischemia.These vascular disorders may occur in a patient undergoing carotidendarterectomy specifically or other cerebrovascular or vascularsurgical procedures in general, or diagnostic vascular proceduresincluding cerebral angiography and the like. Other incidents are headtrauma, spinal cord trauma, or injury from general anoxia, hypoxia,hypoglycemia, hypotension as well as similar injuries seen duringprocedures from embole, hyperfusion, and hypoxia. The instant inventionwould be useful in a range of incidents, for example, during cardiacbypass surgery, in incidents of intracranial hemorrhage, in perinatalasphyxia, in cardiac arrest, and status epilepticus.

A skilled physician will be able to determine the appropriate situationin which subjects are susceptible to or at risk of, for example, strokeas well as suffering from stroke for administration by methods of thepresent invention.

TTX-S sodium channels have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention have utility in treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with TTX-S sodiumchannels, including one or more of the following conditions or diseases:pain, acute pain, chronic pain, neuropathic pain, inflammatory pain,visceral pain, nociceptive pain, multiple sclerosis, neurodegenerativedisorder, irritable bowel syndrome, osteoarthritis, rheumatoidarthritis, neuropathological disorders, functional bowel disorders,inflammatory bowel diseases, pain associated with dysmenorrhea, pelvicpain, cystitis, pancreatitis, migraine, cluster and tension headaches,diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgiaCrohn's disease, epilepsy or epileptic conditions, bipolar depression,tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorderssuch as anxiety and depression, myotonia, arrhythmia, movementdisorders, neuroendocrine disorders, ataxia, incontinence, visceralpain, trigeminal neuralgia, herpetic neuralgia, general neuralgia,postherpetic neuralgia, radicular pain, sciatica, back pain, head orneck pain, severe or intractable pain, breakthrough pain, postsurgicalpain, stroke, cancer pain, seizure disorder and causalgia.

The dosage of active ingredient in the compositions of this inventionmay be varied, however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The activeingredient may be administered to patients (animals and human) in needof such treatment in dosages that will provide optimal pharmaceuticalefficacy.

The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize.

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 0.1 mg to 1000 mgdepending, of course, on the mode of administration. For example, oraladministration may require a total daily dose of from 1 mg to 1000 mg,while an intravenous dose may only require from 0.1 mg to 100 mg. Thetotal daily dose may be administered in single or divided doses and may,at the physician's discretion, fall outside of the typical range givenherein.

These dosages are based on an average human subject having a weight ofabout 60 kg to 70 kg. The physician will readily be able to determinedoses for subjects whose weight falls outside this range, such asinfants and the elderly.

For the avoidance of doubt, references herein to “treatment” includereferences to curative, palliative and prophylactic treatment.

In one embodiment, the dosage range will be about 0.5 mg to 500 mg perpatient per day; in another embodiment about 0.5 mg to 200 mg perpatient per day; in another embodiment about 1 mg to 100 mg per patientper day; and in another embodiment about 5 mg to 50 mg per patient perday; in yet another embodiment about 1 mg to 30 mg per patient per day.Pharmaceutical compositions of the present invention may be provided ina solid dosage formulation such as comprising about 0.5 mg to 500 mgactive ingredient, or comprising about 1 mg to 250 mg active ingredient.The pharmaceutical composition may be provided in a solid dosageformulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg,200 mg or 250 mg active ingredient. For oral administration, thecompositions may be provided in the form of tablets containing 1.0 to1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25,50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, such as once or twiceper day.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention isenvisioned. However, the combination therapy may also include therapiesin which the compound of the present invention and one or more otherdrugs are administered on different overlapping schedules. It is alsocontemplated that when used in combination with one or more other activeingredients, the compounds of the present invention and the other activeingredients may be used in lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present inventioninclude those that contain one or more other active ingredients, inaddition to a compound of the present invention. The above combinationsinclude combinations of a compound of the present invention not onlywith one other active compound, but also with two or more other activecompounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is envisioned. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, including about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

A TTX-S sodium channels blocker may be usefully combined with anotherpharmacologically active compound, or with two or more otherpharmacologically active compounds, particularly in the treatment ofinflammatory, pain and urological diseases or disorders. For example, aTTX-S sodium channels blocker, particularly a compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof, as definedabove, may be administered simultaneously, sequentially or separately incombination with one or more agents selected from:

-   -   an opioid analgesic, e.g. morphine, heroin, hydromorphone,        oxymorphone, levorphanol, levallorphan, methadone, meperidine,        fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,        hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,        naltrexone, buprenorphine, butorphanol, nalbuphine or        pentazocine;    -   a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,        diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,        flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,        ketorolac, meclofenamic acid, mefenamic acid, meloxicam,        nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,        oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,        tolmetin or zomepirac;    -   a barbiturate sedative, e.g. amobarbital, aprobarbital,        butabarbital, butabital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobartital, secobarbital,        talbutal, theamylal or thiopental;    -   a benzodiazepine having a sedative action, e.g.        chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,        oxazepam, temazepam or triazolam;    -   an H1 antagonist having a sedative action, e.g. diphenhydramine,        pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;    -   a sedative such as glutethimide, meprobamate, methaqualone or        dichloralphenazone;    -   a skeletal muscle relaxant, e.g. baclofen, carisoprodol,        chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;    -   an NMDA receptor antagonist, e.g. dextromethorphan        ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan        ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,        pyrroloquinoline quinine,        cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,        EN-3231 (MorphiDex®, a combination formulation of morphine and        dextromethorphan), topiramate, neramexane or perzinfotel        including an NR2B antagonist, e.g. ifenprodil, traxoprodil or        (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;    -   an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,        guanfacine, dexmetatomidine, modafinil, or        4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;    -   a tricyclic antidepressant, e.g. desipramine, imipramine,        amitriptyline or nortriptyline;    -   an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate        or valproate;    -   a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1        antagonist, e.g.        (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione        (TAK-637),        5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino-1]-2-phenylpiperidine        (2S,3S);    -   a muscarinic antagonist, e.g oxybutynin, tolterodine,        propiverine, tropsium chloride, darifenacin, solifenacin,        temiverine and ipratropium;    -   a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;    -   a coal-tar analgesic, in particular paracetamol;    -   a neuroleptic such as droperidol, chlorpromazine, haloperidol,        perphenazine, thioridazine, mesoridazine, trifluoperazine,        fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,        quetiapine, sertindole, aripiprazole, sonepiprazole,        blonanserin, iloperidone, perospirone, raclopride, zotepine,        bifeprunox, asenapine, lurasidone, amisulpride, balaperidone,        palindore, eplivanserin, osanetant, rimonabant, meclinertant,        Miraxion® or sarizotan;    -   a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist        (e.g. capsazepine);    -   a beta-adrenergic such as propranolol;    -   a local anaesthetic such as mexiletine;    -   a corticosteroid such as dexamethasone;    -   a 5-HT receptor agonist or antagonist, particularly a 5-HT1B/1D        agonist such as eletriptan, sumatriptan, naratriptan,        zolmitriptan or rizatriptan;    -   a 5-HT2A receptor antagonist such as        R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol        (MDL-100907);    -   a cholinergic (nicotinic) analgesic, such as ispronicline        (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine        (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine        (ABT-594) or nicotine;    -   Tramadol®;    -   a PDEV inhibitor, such as

-   5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (sildenafil),

-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazin    o[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil),

-   2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one    (vardenafil),

-   5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

-   5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

-   5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

-   4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,

-   3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;    -   an alpha-2-delta ligand such as gabapentin, pregabalin,        3-methylgabapentin,        (1alpha,3alpha,5alpha)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic        acid, (3S,5R)-3 aminomethyl-5 methyl-heptanoic acid, (3S,5R)-3        amino-5 methyl-heptanoic acid, (3S,5R)-3 amino-5 methyl-octanoic        acid, (2S,4S)-4-(3-chlorophenoxy)proline,        (2S,4S)-4-(3-fluorobenzyl)-proline,        [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,        3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,        C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,        (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,        (3S,5R)-3 aminomethyl-5 methyl-octanoic acid, (3S,5R)-3 amino-5        methyl-nonanoic acid, (3S,5R)-3 amino-5 methyl-octanoic acid,        (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and        (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;    -   a cannabinoid;    -   metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;    -   a serotonin reuptake inhibitor such as sertraline, sertraline        metabolite demethylsertraline, fluoxetine, norfluoxetine        (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine,        citalopram, citalopram metabolite desmethylcitalopram,        escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,        cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine        and trazodone;    -   a noradrenaline (norepinephrine) reuptake inhibitor, such as        maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,        tomoxetine, mianserin, buproprion, buproprion metabolite        hydroxybuproprion, nomifensine and viloxazine (Vivalan®,        especially a selective noradrenaline reuptake inhibitor such as        reboxetine, in particular (S,S)-reboxetine;    -   a dual serotonin-noradrenaline reuptake inhibitor, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine, milnacipran and imipramine;    -   an inducible nitric oxide synthase (iNOS) inhibitor such as        S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,        S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,        S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,        (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic        acid,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile;        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,        (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3        pyridinecarbonitrile,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,        N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,        or guanidinoethyldisulfide;    -   an acetylcholinesterase inhibitor such as donepezil;    -   a prostaglandin E2 subtype 4 (EP4) antagonist such as        N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide        or        4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic        acid;    -   a leukotriene B4 antagonist; such as

-   1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic    acid (CP-105696),

-   5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric    acid (ONO-4057) or DPC-11870,    -   a 5-lipoxygenase inhibitor, such as zileuton,        6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-meth        yl-2-quinolone (ZD-2138), or        2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);    -   a sodium channel blocker, such as lidocaine;    -   a 5-HT3 antagonist, such as ondansetron;

and the pharmaceutically acceptable salts and solvates thereof.

Such combinations offer significant advantages, including synergisticactivity, in therapy.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orally administratecompositions are generally preferred. Tablets and capsules for oraladministration may be in unit dose form, and may contain conventionalexcipients, such as binding agents (e.g. pregelatinised maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.lactose, microcrystalline cellulose or calcium hydrogen phosphate);tabletting lubricants (e.g. magnesium stearate, talc or silica);disintegrants (e.g. potato starch or sodium starch glycollate); andacceptable wetting agents (e.g. sodium lauryl sulphate). The tablets maybe coated according to methods well known in normal pharmaceuticalpractice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents (e.g. sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g. lecithin or acacia), non-aqueous vehicles (which may includeedible oils e.g. almond oil, oily esters, ethyl alcohol or fractionatedvegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoatesor sorbic acid), and, if desired, conventional flavourings or colorants,buffer salts and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound or pharmaceutically acceptable salt thereof.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of formula (I) or pharmaceutically acceptable saltthereof and a sterile vehicle. Formulations for injection may bepresented in unit dosage form e.g. in ampoules or in multi-dose,utilising a compound of formula (I) or pharmaceutically acceptable saltthereof and a sterile vehicle, optionally with an added preservative.The compositions may take such forms as suspensions, solutions oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising and/or dispersing agents.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. The compound, depending on the vehicle and concentrationused, can be either suspended or dissolved in the vehicle. In preparingsolutions, the compound can be dissolved for injection and filtersterilised before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are dissolved in the vehicle. To enhance the stability,the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parenteral suspensions are prepared insubstantially the same manner, except that the compound is suspended inthe vehicle instead of being dissolved, and sterilisation cannot beaccomplished by filtration. The compound can be sterilised by exposureto ethylene oxide before suspension in a sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may also be formulated in rectal compositions such assuppositories or retention enemas, e.g. containing conventionalsuppository bases such as cocoa butter or other glycerides.

The compounds of formula (I) or pharmaceutically acceptable salts mayalso be formulated as depot preparations. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds of formula (I) or pharmaceutically acceptable salts may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

For intranasal administration, the compounds formula (I) orpharmaceutically acceptable salts thereof may be formulated as solutionsfor administration via a suitable metered or unitary dose device oralternatively as a powder mix with a suitable carrier for administrationusing a suitable delivery device. Thus compounds of formula (I) orpharmaceutically acceptable salts thereof may be formulated for oral,buccal, parenteral, topical (including ophthalmic and nasal), depot orrectal administration or in a form suitable for administration byinhalation or insufflation (either through the mouth or nose). Thecompounds of formula (I) and pharmaceutically acceptable salts thereofmay be formulated for topical administration in the form of ointments,creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear ornose drops). Ointments and creams may, for example, be formulated withan aqueous or oily base with the addition of suitable thickening and/orgelling agents. Ointments for administration to the eye may bemanufactured in a sterile manner using sterilized components.

General Synthesis

Throughout the instant application, the following abbreviations are usedwith the following meanings:

DMF: N,N-dimethylformamide

TLC: Thin layer chromatography

HBTU: N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate

DTAD: di-tert-butyl azodicarboxylate

mCPBA: m-chloroperbenzoic

TMSCN: trimethylsilyl cyanide

WSC: 1-ethyl-3-((3-dimethylaminopropyl)carbodiimide hydrochloride

HOBT: 1-hydroxybenzotriazole hydrate

DMSO: dimethylsulfoxide

XANTPHOS: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium

The term of “base” is likewise no particular restriction on the natureof the bases used, and any base commonly used in reactions of this typemay equally be used here. Examples of such bases include: alkali metalhydroxides, such as lithium hydroxide, sodium hydroxide, potassiumhydroxide, and barium hydroxide; alkali metal hydrides, such as lithiumhydride, sodium hydride, and potassium hydride; alkali metal alkoxides,such as sodium methoxide, sodium ethoxide, and potassium t-butoxide;alkali metal carbonates, such as lithium carbonate, sodium carbonate,potassium carbonate, and cesium carbonate; alkali metalhydrogencarbonates, such as lithium hydrogencarbonate, sodiumhydrogencarbonate, and potassium hydrogencarbonate; amines, such asN-methylmorpholine, triethylamine, tripropylamine, tributylamine,diisopropylethylamine, N-methylpiperidine, pyridine,4-pyrrolidinopyridine, picoline, 2,6-di(t-butyl)-4-methylpyridine,quinoline, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lutidine, andcolidine; alkali metal amides, such as lithium amide, sodium amide,potassium amide, lithium diisopropyl amide, potassium diisopropyl amide,sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassiumbis(trimethylsilyl)amide. Of these, triethylamine,diisopropylethylamine, DBU, DBN, DABCO, pyridine, lutidine, colidine,sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassiumcarbonate, potassium hydrogencarbonate, potassium hydroxide, bariumhydroxide, and cesium carbonate are preferred.

The reactions are normally and preferably effected in the presence ofinert solvent. There is no particular restriction on the nature of thesolvent to be employed, provided that it has no adverse effect on thereaction or the reagents involved and that it can dissolve reagents, atleast to some extent. Examples of suitable solvents include, but notlimited to: halogenated hydrocarbons, such as dichloromethane,chloroform, carbon tetrachloride, and dichloroethane; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF), and dioxane;aromatic hydrocarbons, such as benzene, toluene and nitrobenzene;amides, such as, DMF, N,N-dimethylacetamide, and hexamethylphosphorictriamide; amines, such as N-methylmorpholine, triethylamine,tripropylamine, tributylamine, diisopropylethylamine,N-methylpiperidine, pyridine, 4-pyrrolidinopyridine,N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol,ethanol, propanol, isopropanol, and butanol; nitriles, such asacetonitrile and benzonitrile; sulfoxides, such as DMSO and sulfolane;ketones, such as acetone and diethylketone. Of these solvents, includingbut not limited to DMF, DMSO, THF, diethylether, diisopropylether,dimethoxyethane, acetonitrile, dichloromethane, dichloroethane andchloroform are preferred.

The term “protecting group”, as used hereinafter, means a hydroxy,carboxy, or amino-protecting group which is selected from typicalhydroxy, carboxy, or amino-protecting groups described in ProtectiveGroups in Organic Synthesis edited by T. W. Greene et al. (John Wiley &Sons, 1999). All starting materials in the following general synthesesmay be commercially available or obtained by conventional methods knownto those skilled in the art, such as European Journal of MedicinalChemistry, 12 (1), 87-91; 1977 and the disclosures of which areincorporated herein by reference.

All of the picolinamide derivatives of the formula (I) can be preparedby the procedures described in the general methods presented below or bythe specific methods described in the Examples section and thePreparations section, or by routine modifications thereof. The presentinvention also encompasses any one or more of these processes forpreparing the picolinamide derivatives of formula (I), in addition toany novel intermediates used therein.

In the following general methods, Y, R¹, R², R³, and R⁴ are aspreviously defined for picolinamide derivatives of the formula (I)unless otherwise stated.

The preparation of compounds of formula (I) of the present invention canbe carried out in sequential or convergent synthetic routes.

Syntheses detailing the preparation of the compounds of formula (I) in asequential manner are presented in the following reaction schemes. Thephrase “standard peptide coupling reaction conditions” is usedrepeatedly here, and it means coupling a carboxylic acid with an amineusing an acid activating agent such as EDC, DCC, HBTU, and BOP in ainert solvent such as DMF, acetonitrile, and dichloromethane in thepresence of a catalyst such as HOBT and/or in the presence of a basesuch as triethylamine, diisopropylethylamine.

The following illustrates a preparation of the desired compound offormula I (Scheme 1).

In Scheme 1, PG¹ is a hydroxy-protecting group or absent and X is aleaving group commonly used for peptide coupling reaction and Y, R¹, R²,R³ and R⁴ are as defined above.

The term “hydroxy-protecting group”, as used herein, signifies aprotecting group capable of being cleaved by chemical means, such as(hydrogenolysis, hydrolysis, electrolysis, or photolysis and such ashydroxy-protecting groups are described in Protective Groups in OrganicSynthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999).Typical hydroxy-protecting groups include, but not limited to: methyl,CH₃OCH₂—, CH₃SCH₂—, benzyl, p-methoxybenzyl, benxyloxylmethyl, benzoyl,acetyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, andt-butyldiphenylsilyl. Of these groups, t-butyldimethylsilyl andbezyloxymethyl are preferred.

The term “a leaving group of the commonly used for peptide couplingreaction” as used herein, signifies, such as but no limited to: halide,acid anhydride, imidazole, and azide.

When R⁴ is hydroxy group and PG¹ is hydroxy-protecting group, thecompound of formula I can be prepared from a compound of formula II bycoupled with an activated ester compound of formula III and followingdeprotection of PG¹. The coupling reaction is carried out with presenceof the suitable base such as triethylamine in a suitable solvent such asdichloromethane at a temperature of from about −10 to about 70° C. forabout 5-20 hours. This deprotection reaction method is described indetail by T. W. Greene et al. [Protective Groups in Organic Synthesis,(1999)], the disclosures of which are incorporated herein by reference.The following is a typical method, provided the protecting groups aret-butyldimethylsilyl and benzyloxymethyl.

The deprotection reaction is carried out in the presence of an acid.There is likewise no particular restriction on the nature of the acidsused, and any acid commonly used in reactions of this type may equallybe used here. Examples of such acids include, but are not limited to:acids, such as trifluoroacetic acid and trifluoromethanesulfonic acid,or hydrogen halide such as HCl, HBr, and HI.

The deprotection reaction is normally and preferably effected in thepresence of solvent. There is no particular restriction on the nature ofthe solvent to be employed, provided that it has no adverse effect onthe reaction or the reagents involved and that it can dissolve reagents,at least to some extent. Examples of suitable solvents include, but arenot limited to: halogenated hydrocarbons, such as dichloromethane,chloroform, carbon tetrachloride, and dichloroethane; ethers, such asdiethyl ether, diisopropyl ether, THF, and dioxane, esters such as ethylacetate, alcohols such as methanol, ethanol, propanol, isopropanol, andbutanol, water and aromatic hydrocarbons, such as benzene, toluene, andnitrobenzene. Of these solvents, dichloromethane, dichloroethane,chloroform, water, alcohol, THF, and ethyl acetate are preferred.

When R⁴ is not hydroxy group and PG¹ is absent, the compound of formulaI can be prepared from a compound of formula II by coupling with anactivated ester compound of formula III as defined above.

When R⁴ is hydroxy group and PG¹ is hydroxy-protecting group, thecompound of formula I can be also prepared by peptide coupling reactionand following PG¹ deprotection reaction. In the case of PG¹ is absent,the compound of formula I can be prepared by the same method asdescribed above without PG¹ deprotection reaction. The coupling reactionof the compound of formula II and IV can be carried out by usingstandard peptide coupling reaction conditions as defined above. Themethod of following PG¹ deprotection reaction is described in above.

When R⁴ is not hydroxy group and PG¹ is absent, the compound of formulaI can be prepared from a compound of formula II and IV by utilizingstandard peptide coupling reaction conditions as defined above.

The following illustrates an alternative preparation of the desiredcompound of formula I (Scheme 2).

In Scheme 2, Y, PG¹, R¹, R², R³ and R⁴ are as defined above.

When R⁴ is hydroxy group and PG¹ is hydroxy-protecting group, thecompound of formula I can be prepared from the compound of formula V bypartially hydrolysis of nitrile and following or same time PG¹deprotection reaction. In the case of PG¹ is absent, the compound offormula I can be prepared by the same method as described above withoutPG¹ deprotection reaction.

When R⁴ is not hydroxy group and PG¹ is absent, the compound of formulaI can be prepared from the compound of formula V by partially hydrolysisof nitrile.

The partially hydrolysis of nitrile and/or PG¹ deprotection reaction iscarried out in the presence of base. There is likewise no particularrestriction on the nature of the bases used, and any base commonly usedin reactions of this type may equally be used here. Examples of suchbase include, but are not limited to: metal hydroxide, such as sodiumhydroxide and potassium hydroxide: metal carbonate with hydrogenperoxide, such as potassium carbonate with hydrogen peroxide.

This reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but not limited to:alcohols, such as methanol, ethanol, propanol, isopropanol, andt-butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides,such as dimethyl sulfoxide and sulfolane. Of these solvents, t-butanol,acetonitrile, and dimethyl sulfoxide are preferred.

This reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout −10° C. to about 85° C., more preferably from about 0° C. to about70° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the starting materials and solvent employed. However, providedthat the reaction is effected under the preferred conditions outlinedabove, a period of from about 5 minutes to about 48 hours.

The partially hydrolysis of nitrile and/or PG¹ deprotection reaction isalso carried out in the presence of acid. There is likewise noparticular restriction on the nature of the acids used, and any acidscommonly used in reactions of this type may equally be used here.Examples of such acid include, but are not limited to: inorganic acid,such as hydrochloric acid, sulfuric acid, and polyphosphoricacid:combination acid, such as sulfuric acid with acetic acid, borontrifluoride with aqueous acetic acid.

This reaction is normally and preferably effected in the absence ofsolvent.

This reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the acids, and the starting materials. However, in general, itis convenient to carry out the reaction at a temperature of from about20° C. to about 150° C., more preferably from about 40° C. to about 140°C. The time required for the reaction may also vary widely, depending onmany factors, notably the reaction temperature and the nature of thestarting materials and solvent employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from about 5 minutes to about 48 hours.

In the following PG¹ deprotection reaction is needed, the method of PG¹deprotection reaction is described in above.

The following illustrates an alternative preparation of the desiredcompound of formula I (Scheme 3).

In Scheme 3, LG¹ is leaving group, Y, PG¹, R¹, R², R³ and R⁴ are asdefined above.

The term “leaving group”, as used herein, signifies a group capable ofbeing substitued by nucleophilic groups, such as a hydroxy group,amines, or carboanions and examples of such leaving groups includehalogen atoms, an alkylsulfonyl group and an arylsulfonyl group. Ofthese, an iodine atom, a bromine atom, a chlorine atom, atrifluoromethanesulfonyl group, a p-toluenesulfonyl, and a phenysulfonylare preferred.

When R⁴ is hydroxy group and PG¹ is hydroxy-protecting group, thecompound of formula Ib (R² is not hydrogen atom) can be prepared fromthe compound of formula Ia (R² is hydrogen atom) with R²—LG¹ bypalladium catalyzed coupling reaction or nucleophilic substitutionreaction and following PG¹ deprotection reaction. In the case of PG¹ isabsent, the compound formula Ib (R² is not hydrogen atom) can beprepared by the same method as described above without PG¹ deprotectionreaction.

When R⁴ is not hydroxy group and PG¹ is absent, the compound of formulaIb can be prepared from the compound of formula Ia by the same method asdescribed above without PG¹ deprotection reaction.

This palladimun catalyzed coupling reaction method is described indetail by Ligthart, G. B. et al. Journal of Organic Chemistry, 375, 71,2006, the disclosures of which are incorporated herein by reference.

This nucleophilic substitution reaction is carried out in the presenceof suitable base. There is likewise no particular restriction on thenature of the bases used, and any base commonly used in reactions ofthis type may equally be used here. Examples of such base include, butare not limited to: metal hydride, such as sodium hydride and potassiumhydride: metal amide, such as lithium N,N-diisopropylamide.

This reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but not limited to:halogenated hydrocarbons, such as dichloromethane, chloroform, carbontetrachloride, and dichloroethane; ethers, such as diethyl ether,diisopropyl ether, THF, dimethoxyethane, and dioxane; aromatichydrocarbons, such as benzene, toluene, xylene, chlorobenzene,dichlorobenzene, and nitrobenzene; amides, such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, and hexamethylphosphorictriamide; nitriles, such as acetonitrile and benzonitrile; sulfoxides,such as dimethyl sulfoxide, and sulfolane. Of these solvents, THF,dimethoxyethane, acetonitrile, dimethyl sulfoxide are preferred.

This reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout −10° C. to about 150° C., more preferably from about 0° C. toabout 100° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the starting materials and solvent employed. However, providedthat the reaction is effected under the preferred conditions outlinedabove, a period of from about 5 minutes to about 100 hours.

The following illustrates an alternative preparation of the desiredcompound of formula I (Scheme 4).

In Scheme 4, X, Y, PG¹, R¹, R², R³ and R⁴ are as defined above and LG²is a leaving group using for the formation of activated ester, such asbut not limited to: halo oxalyl group of oxalyl halide, halo thionygroup of thionyl halide, halide of halo alkylformate, N-imidazoylcarbonygroup of N,N′-carbonydiimidazole, and diphenylphosphoryl group ofdiphenylphosphoryl azide.

The compound of formula VI is prepared by deprotection reaction fromcompound of formula XIVc wherein PG¹ is a carboxy-protecting group.

When R⁴ is hydroxy group and PG¹ is hydroxy-protecting group, thecompound of formula I can be prepared by peptide coupling reaction andfollowing PG¹ deprotection reaction. The coupling reaction of thecompound of formula VI and an amine compound of R²—NH₂ can be carriedout by using standard peptide coupling reaction conditions and themethod of PG¹ deprotection reaction were described in above. In the caseof PG¹ is absent, the compound of formula I can be prepared by the samemethod as described above without PG¹ deprotection reaction.

When R⁴ is not hydroxy group and PG¹ is absent, the compound of formulaI can be prepared from a compound of formula VI and an amine compoundR²—NH₂ by the same manner as defined above without PG¹ deprotectionreaction.

The desired compound of formula of I can be prepared by the alternativeroutes.

When R⁴ is hydroxy group and PG¹ is hydroxy-protecting group, thecompound of formula I can be prepared by peptide coupling reaction viaan activated ester, and following PG¹ deprotection reaction. Theactivated ester can be prepared from the compound of formula VI andLG²-X with or without suitable base. The compound of formula I can beprepared from the activated ester and an amine compound of R²—NH₂ withsuitable base and following PG¹ deprotection reaction.

When R⁴ is not hydroxy group and PG¹ is absent, the compound of formulaI can be prepared from a compound of formula VI via an activated esterand an amine compound R²—NH₂ by the same manner as defined above withoutPG¹ deprotection reaction.

The following illustrates a preparation of the intermediate of formulaII via amino-protected compound of formula VIIb (R² is not hydrogenatom) (Scheme 5).

In Scheme 5, PG² is an amino-protecting group, LG¹, PG¹, Y, R¹, R², R³and R⁴ are as defined above.

The term “amino-protecting group”, as used herein, signifies aprotecting group capable of being cleaved by chemical means, such ashydrogenolysis, hydrolysis, electrolysis or photolysis and suchamino-protecting groups are described in Protective Groups in OrganicSynthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999).Typical amino-protecting groups include benzyl, C₂H₅O(C═O)—, CH₃(C═O)—,benzyloxycarbonyl and t-butoxycarbonyl. Of these groups,t-butoxycarbonyl is preferred.

When R⁴ is hydroxy group and PG¹ is present or absent, the compound offormula VIIb (R² is not hydrogen atom) can be prepared from the compoundof formula VIIa (R² is hydrogen atom) with R²—LG¹ by palladium catalyzedcoupling or nucleophilic substitution reaction.

When R⁴ is not hydroxy group and PG¹ is absent, the compound of formulaVIIb can be prepared from the compound of formula VIIa by the samemethod as described above.

This palladimun catalyzed coupling or nucleophilic substitution reactioncan be carried out by the same procedures as described in Scheme 4.

The desired intermediate, compound of formula II can be prepared bydeprotection of amino-protecting group with or without PG1 deprotectionreaction in same time of the compound of formula VIIb (R² is nothydrogen atom).

This deprotection method is described in detail by T. W. Greene et al.[Protective Groups in Organic Synthesis, 494-653, (1999)], thedisclosures of which are incorporated herein by reference. The followingis a typical method, provided the protecting group is t-butoxycarbonyl.

The deprotection is carried out in the presence of an acid. There islikewise no particular restriction on the nature of the acids used, andany acid commonly used in reactions of this type may equally be usedhere. Examples of such acids include, but are not limited to: acids,such as trifluoroacetic acid and trifluoromethanesulfonic acid, orhydrogen halide such as HCl, HBr, and HI.

The deprotection is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but are not limitedto: halogenated hydrocarbons, such as dichloromethane, chloroform,carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether,diisopropyl ether, THF, and dioxane, esters such as ethyl acetate,alcohols such as methanol, ethanol, propanol, isopropanol, and butanol,water and aromatic hydrocarbons, such as benzene, toluene, andnitrobenzene. Of these solvents, dichloromethane, dichloroethane,chloroform, water, alcohol, THF, and ethyl acetate are preferred.

The following illustrates a preparation of the intermediate of formula Xby ether formation reaction of compound of formula VIII and IX (Scheme6).

In Scheme 6, X¹ and X² are a leaving groups and/or hydroxy group, LG¹,PG², PG³, Y, R¹, and R⁴ are as defined above and PG¹ ishydroxy-protecting group, R^(xx) is hydrogen, nitrile, carboxamide,CO₂PG³.

The term “leaving group”, as used herein, signifies a group capable ofbeing substitued by nucleophilic groups, such as a hydroxy group,amines, or carboanions and examples of such leaving groups includehalogen atoms, an alkylsulfonyl group and an arylsulfonyl group. Ofthese, a bromine atom, a chlorine atom, methanesulfonyl group,p-toluenesulfonyl group are preferred.

When leaving groups, X¹ and X² are hydroxy group, the desired compoundof formula X can be prepared by Mitsunobu reaction.

Mitsunobu reaction is carried out in the presence of reagent(s). Thereis likewise no particular restriction on the nature of the reagentsused, and any reagent commonly used in reactions of this type mayequally be used here. Examples of such reagents include but not limitedto:

(a) a combination of (a1) dialkyl azodicarboxylate such as diethylazodicarboxylate (DEAD), dimethyl azodicarboxylate (DMAD) anddiisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate(DTAD) and (a2) trialkylphosphine such as tributylphosphine (TBP) ortriarylphosphine such as triphenylphosphine (TPP);

(b) a combination of (b1) tetraalkylazodicarboxamide such asN,N,N′,N′-tetraisopropylazodicarboxamide (TIPA) andN,N,N′,N′-tetramethylazodicarboxamide (TMAD) and (b2) trialkylphosphinesuch as TBP or triarylphosphine such as TPP;

(c) phosphorane such as cyanomethylenetributylphosphorane (CMBP),cyanomethylenetrimethylphosphorane and dimethyl(tributylphosphoranylidene)malonate (DMTP).

The coupling reaction can take place over a wide range of temperatures,and the precise reaction temperature is not critical to the invention.The preferred reaction temperature will depend upon such factors as thenature of the solvent, the starting materials and reagents used. It isconvenient to carry out the reaction at a temperature of from about −78°C. to about 25° C. for reagents (a) and about 50° C. to about 100° C.for reagents (b) and (c). The time required for the reaction may alsovary widely, depending on many factors, notably the reaction temperatureand the nature of the starting materials and solvent employed. However,provided that the reaction is effected under the preferred conditionsoutlined above, a period of from about 30 minutes to about 24 hours.

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but not limited to:aliphatic hydrocarbons, such as hexane, heptane, and petroleum ether;halogenated hydrocarbons, such as dichloromethane, chloroform, carbontetrachloride, and dichloroethane; ethers, such as diethyl ether,diisopropyl ether, THF, dimethoxyethane, and dioxane; aromatichydrocarbons, such as benzene, toluene, xylene, chlorobenzene,dichlorobenzene, and nitrobenzene; amides, such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, and hexamethylphosphorictriamide; amines, such as N-methylmorpholine, triethylamine,tripropylamine, tributylamine, diisopropylethylamine, pyridine,4-pyrrolidinopyridine, N,N-dimethylaniline, and N,N-diethylaniline;nitriles, such as acetonitrile and benzonitrile; sulfoxides, such asdimethyl sulfoxide, and sulfolane. Of these solvents, toluene, benzene,xylene, chlorobenzene, dichlorobenzene, THF, diethylether,diisopropylether, dimethoxyethane, acetonitrile, dichloromethane,dichloroethane, and chloroform are preferred.

In the case of X¹ is leaving group as defined above and X² is hydroxygroup or X¹ is hydroxy group and X² is leaving group as defined above,the desired compound of formula X can be prepared by nuculeophilicsubstitution reaction with presence a suitable base.

This reaction is carried out in the presence of a base. There islikewise no particular restriction on the nature of the bases used, andany base commonly used in reactions of this type may equally be usedhere. Examples of such bases include: alkali metal hydroxides, such aslithium hydroxide, sodium hydroxide, potassium hydroxide, and bariumhydroxide; alkali metal hydrides, such as lithium hydride, sodiumhydride, and potassium hydride; alkali metal alkoxides, such as sodiummethoxide, sodium ethoxide, and potassium t-butoxide; alkali metalcarbonates, such as lithium carbonate, sodium carbonate, potassiumcarbonate, and cesium carbonate; alkali metal hydrogen-carbonates, suchas lithium hydrogencarbonate, sodium hydrogencarbonate, and potassiumhydrogencarbonate; amines, such as N-methylmorpholine, triethylamine,tripropylamine, tributylamine, diisopropylethylamine,N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,N,N-diethylaniline, DBN, DABCO, DBU, lutidine, and colidine; alkalimetal amides, such as lithium amide, sodium amide, potassium amide,lithium diiropropyl amide, potassium diisopropyl amide, sodiumdiiropropyl amide, lithium bis(trimethylsilyl)amide and potassiumbis(trimethylsilyl)amide. Of these, sodium carbonate, potassiumcarbonate, and cesium carbonate are preferred.

This reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, the starting materials and reagents used. It isconvenient to carry out the reaction at a temperature of from about 0°C. to about 100° C. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the starting materials and solvent employed. However,provided that the reaction is effected under the preferred conditionsoutlined above, a period of from about 1 hours to about 24 hours.

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but not limited to:a halogenated hydrocarbons, such as dichloromethane, chloroform, carbontetrachloride, and dichloroethane; ethers, such as diethyl ether,diisopropyl ether, THF, dimethoxyethane, and dioxane; aromatichydrocarbons, such as benzene, toluene, xylene, chlorobenzene,dichlorobenzene, and nitrobenzene; amides, such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone,and hexamethylphosphoric triamide; amines, such as N-methylmorpholine,triethylamine, tripropylamine, tributylamine, diisopropylethylamine,pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, andN,N-diethylaniline; nitriles, such as acetonitrile and benzonitrile;sulfoxides, such as dimethyl sulfoxide, and sulfolane. Of thesesolvents, THF, N,N-dimethylformamide, dimethyl sulfoxide andN-methyl-2-pyrrolidinone are preferred.

The following illustrates an alternative preparation of the intermediateof formula Xb (R^(xx) is nitrile) from the compound of formula Xa(R^(xx) is hydrogen) (Scheme 7).

In the Scheme 7, R^(xx) is not hydroxy group, PG¹, PG², Y, R¹, and R⁴are as defined above.

The desired intermediate of the formula Xb (R^(xx) is nitrile) can beprepared by cyanation of the compound of formula XI. The compound offormula XI can be prepared by N-oxidation by utilizing suitable oxidant,such as m-chloroperbenzoic acid and hydrogen peroxide.

This N-oxidation reaction can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. The preferred reaction temperature will depend upon suchfactors as the nature of the solvent, the starting materials andreagents used. It is convenient to carry out the reaction at atemperature of from about −50° C. to about 50° C. The time required forthe reaction may also vary widely, depending on many factors, notablythe reaction temperature and the nature of the starting materials andsolvent employed. However, provided that the reaction is effected underthe preferred conditions outlined above, a period of from about 5minutes to about 24 hours.

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but not limited to:a halogenated hydrocarbons, such as dichloromethane, chloroform, carbontetrachloride, and dichloroethane; aromatic hydrocarbons, such asbenzene, toluene, xylene, chlorobenzene, dichlorobenzene, andnitrobenzene; nitriles, such as acetonitrile and benzonitrile;sulfoxides, such as DMSO. Of these solvents, dichloromethane and DMSOare preferred.

The cyanation is carried out in the presence of reagent(s). There islikewise no particular restriction on the nature of the reagents used,and any reagent commonly used in reactions of this type may equally beused here. Examples of such reagents include but not limited to: silylcyanide, such as trimethylsilyl cyanide, tert-butyldimethylsilylcyanide, tert-butyldiphenylsilyl cyanide, alkali cyanide, such as sodiumcyanide and potassium cyanide.

This cyanation reaction is normally and preferably effected in thepresence of base. There is likewise no particular restriction on thenature of the bases used, and any base commonly used in reactions ofthis type may equally be used here. Examples of such bases include:alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide,potassium hydroxide, and barium hydroxide; alkali metal carbonates, suchas lithium carbonate, sodium carbonate, potassium carbonate, and cesiumcarbonate; alkali metal hydrogencarbonates, such as lithiumhydrogencarbonate, sodium hydrogencarbonate, and potassiumhydrogencarbonate; amines, such as N-methylmorpholine, triethylamine,tripropylamine, tributylamine, diisopropylethylamine,N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,N,N-diethylaniline, DBN, DABCO, DBU, lutidine, and colidine. Of these,amines, triethylamine and alkali metal hydroxides, sodium hydroxide arepreferred.

This reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, the starting materials and reagents used. It isconvenient to carry out the reaction at a temperature of from about 0°C. to about 100° C. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the starting materials and solvent employed. However,provided that the reaction is effected under the preferred conditionsoutlined above, a period of from about 1 hours to about 24 hours.

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but not limited to:a halogenated hydrocarbons, such as dichloromethane, chloroform, carbontetrachloride, and dichloroethane; ethers, such as diethyl ether,diisopropyl ether, THF, dimethoxyethane, and dioxane; aromatichydrocarbons, such as benzene, toluene, xylene, chlorobenzene,dichlorobenzene, and nitrobenzene; amides, such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone,and hexamethylphosphoric triamide; amines, such as N-methylmorpholine,triethylamine, tripropylamine, tributylamine, diisopropylethylamine,pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, andN,N-diethylaniline; nitriles, such as acetonitrile and benzonitrile;sulfoxides, such as dimethyl sulfoxide, and sulfolane. Of thesesolvents, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxideare preferred.

The following illustrates an alternative preparation of the intermediateof formula IIa (R² is hydrogen) from the compound of formula Xb (R^(xx)is nitrile) by nitrile partially hydrolysis and PG² deprotectionreactions with or without same time PG¹ deprotection reaction in thesteps in Scheme 8.

In the Scheme 8, R^(xx) is nitrile, PG¹, PG², Y, R¹, and R⁴ are asdefined above. The intermediate of the compound of formula IIa (R² ishydrogen) can be prepared by partially hydrolysis of nitrile of thecompound of formula Xb (R^(xx) is nitrile) and PG² deprotectionreactions via the intermediate of compound of formula VIIa (R² ishydrogen). The compound of formula IIa (R² is hydrogen) also can beprepared form the compound formula Xb (R^(xx) is nitrile) by PG²deprotection and partially hydrolysis of nitrile of the compound offormula XII.

The conditions of this nitrile partially hydrolysis reaction is asdescribed as description of Scheme 2. The conditions of this PG² with orwithout PG¹ deprotection reaction is as described as description ofScheme 5.

The following illustrates preparation of the intermediate of formula Vfrom the compound of formula XII by peptide bond formation reaction withthe activated ester of the formula III or carboxylic acid of the formulaIV (Scheme 9).

In the Scheme 9, PG¹, Y, R¹, R³, and R⁴ are as defined above. Thecompound of formula V can be prepared by peptide bond formation reactionof amine of the formula XII with activated ester of the formula III orcarboxylic acid of the formula IV.

This peptide bond formation can be carried out by the same procedures asdescribed in Scheme 1.

The following illustrates preparation of the intermediate of formulaXIVc (R^(xx) is CO_(2 PG) ³) from the compound of formula Xc (R^(xx) isCO₂PG³) by PG² (with or without PG³) deprotection, peptide bondformation, and PG³ deprotection reactions (Scheme 10).

In the Scheme 10, R^(xx) is CO₂PG³, PG¹, PG², Y, R¹, R³, and R⁴ are asdefined above, and PG³ is a carboxy-protecting group.

The term “carboxy-protecting group”, as used herein, signifies aprotecting group capable of being cleaved by chemical means, such ashydrogenolysis, hydrolysis, electrolysis, or photolysis, and suchcarboxy-protecting groups are described in Protective Groups in OrganicSynthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999).Typical carboxy-protecting groups include, but are not limited to:methyl, ethyl, t-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl,diphenylmethyl, trimethylsilyl, t-butyldimethylsilyl and allyl. Of thesegroups, ethyl or methyl are preferred.

The compound of formula VI can be prepared from the compound formula Xc(R^(xx) is CO₂PG³) by PG² deprotection, peptide bond formation, andfollowing PG³ deprotection.

Preparation of the Compound of Formula XIII from the Compound Formula Xc(R^(xx) is CO₂PG³) can be carried out PG² deprotection reaction as sameas described in Scheme 5.

The compound of formula XIVc (PG³ is a carboxy-protecting group) can beprepared by peptide bond formation between compound formula XIII andactivated ester of the formula III or carboxylic acid of the formula IV.In this step, the peptide bond formation methods are described asdescription of Scheme 1.

The PG³ deprotection will follow to yield a carboxy group, compound ofthe formula VI. This reaction is described in detail by T. W. Greene etal., Protective Groups in Organic Synthesis, 369-453, (1999), thedisclosures of which are incorporated herein by reference. The followingexemplifies a typical reaction involving the protecting group methyl.

The deprotection is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but are not limitedto: ethers, such as diethyl ether, diisopropyl ether, THF, and dioxane,and alcohols such as methanol, ethanol, propanol, isopropanol, andbutanol. Of these solvents, THF and methanol are preferred.

The deprotection is carried out in the presence of a base. There islikewise no particular restriction on the nature of the bases used, andany base commonly used in reactions of this type may equally be usedhere. Examples of such bases include: alkali metal hydroxides, such aslithium hydroxide, sodium hydroxide, potassium hydroxide, and bariumhydroxide. Of these, sodium hydroxide and potassium hydroxide arepreferred.

The deprotection can take place over a wide range of temperatures, andthe precise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout −20° C. to about 120° C., more preferably from about 0° C. toabout 100° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the starting materials and solvent employed. However, providedthat the reaction is effected under the preferred conditions outlinedabove, a period of from about 30 minutes to about 48 hours.

The following illustrates a preparation of the intermediate of formulaVII from the compound of formula Xc (R^(xx) is CO₂PG³) or XV by peptidebond formation (Scheme 11).

In the Scheme 11, PG¹, PG², PG¹, LG², X, Y, R¹, R², and R⁴ are asdefined above. The desired compound of formula of VII can be prepared bythe direct amidation, which is carried out by reacting the ester offormula Xc and amine of formula R²—NH₂.

In this reaction, direct amidation of ester can take place over a widerange of temperatures, and the precise reaction temperature is notcritical to the invention. The preferred reaction temperature willdepend upon such factors as the nature of the solvent, the startingmaterials and amine used. It is convenient to carry out the reaction ata temperature of from about 50° C. to about 230° C. The time requiredfor the reaction may also vary widely, depending on many factors,notably the reaction temperature and the nature of the startingmaterials and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 1 hours to about 24 hours.

This reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but not limited to:ethers, such as THF, dimethoxyethane, and dioxane; aromatichydrocarbons, such as benzene, toluene, xylene, chlorobenzene,dichlorobenzene, and nitrobenzene; amides, such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone,and hexamethylphosphoric triamide; amines, such as N-methylmorpholine,triethylamine, tripropylamine, tributylamine, diisopropylethylamine,pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, andN,N-diethylaniline; alcohols, such as methanol, ethanol, propanol,isopropanol, and butanol; nitriles, such as acetonitrile andbenzonitrile; sulfoxides, such as dimethyl sulfoxide, and sulfolane. Ofthese solvents, methanol, N,N-dimethylformamide,N-methyl-2-pyrrolidinone, and dimethyl sulfoxide are preferred.

The desired compound of formula of VII can be prepared by thealternative routes.

In the case of the starting material is compound of formula Xc (R^(xx)is CO₂PG³). The desired compound of formula VII can be prepared by PG³deprotection and following peptide bond formation with amine of formulaR²—NH₂ via intermediate of formula XV.

The PG³ deprotection reaction will follow to yield a carboxy group byusing the similar method described in Scheme 10.

The peptide bond formation reaction is carried out by using the samemethods described in Scheme 4.

On the other hands, in the case of the starting material is compound offormula XV. The desired compound of formula VII can be prepared bypeptide bond formation as described above.

The following illustrates a preparation of the intermediate of formulaXIV from the compound of formula XVI by sequence of peptide bondformation and coupling reaction (Scheme 12).

In Scheme 12, R^(xx) is hydrogen atom or CO₂PG³; X², Y, PG³, R¹, R³, andR⁴ are as defined above and PG¹ is hydroxy-protecting group. The desiredcompound, XIV can be prepared by sequential coupling reactions. Thepeptide bond formation reaction can be carried out to obtain thecompound of formula XVII from the compound formula XVI and IV. Thedesired compound of formula XIV can be prepared by following couplingreaction between the compound of formula XVII and IX.

The peptide bond formation reaction is carried out by using the samemethods described in Scheme 1.

The following coupling reaction is carried out by using the same methodsdescribed in Scheme 6.

The following illustrates a preparation of the intermediate of formula Vfrom the compound of formula XIVa (R^(xx) is hydrogen) by the samemanner as described in Scheme 7 (Scheme 13).

In Scheme 13, R^(xx) is hydrogen atom; PG¹, Y, R¹, R³, and R⁴ are asdefined above.

The desired intermediate of the formula V can be prepared by cyanationof the compound of formula XVIII. The compound of formula XVIII can beprepared by N-oxidation reaction.

These reaction methods are utilizing same methods as described in Scheme7.

EXAMPLES

The invention is illustrated in the following non-limiting examples inwhich, unless stated otherwise: all reagents are commercially available,all operations were carried out at room or ambient temperature, that is,in the range of about 18-25° C.; evaporation of solvent was carried outusing a rotary evaporator under reduced pressure with a bath temperatureof up to about 60° C.; reactions were monitored by thin layerchromatography (TLC) and reaction times are given for illustration only;the structure and purity of all isolated compounds were assured by atleast one of the following techniques: TLC (Merck silica gel 60 F254precoated TLC plates or Merck NH2 F2548 precoated HPTLC plates), massspectrometry or nuclear magnetic resonance (NMR). Yields are given forillustrative purposes only. Flash column chromatography was carried outusing Merck silica gel 60 (230-400 mesh ASTM) or Fuji SilysiaChromatorex® DU3050 (Amino Type, 30-50 micrometer) or Biotage silica(32-63 mm, KP-Sil) or Biotage amino bounded silica (35-75 mm, KP—NH).The purification of compounds using HPLC was performed by the followingapparatus and conditions; Apparatus; Waters MS-trigger AutoPurification™system Column; Waters XTerra C18, 19×50 mm, 5 mm particle, solventsystems; Methanol or acetonitrile/0.05% (v/v) formic acid aqueoussolution, or; Methanol or acetonitrile/0.01% (v/v) ammonia aqueoussolution. Low-resolution mass spectral data (ESI) were obtained by thefollowing apparatus and conditions: Apparatus; Waters Alliance HPLCsystem on ZQ or ZMD mass spectrometer and UV detector. NMR data wasdetermined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOLJNM-LA300) using deuterated chloroform (99.8% D) or dimethylsulfoxide(99.9% D) as solvent unless indicated otherwise, relative totetramethylsilane (TMS) as internal standard in parts per million (ppm);conventional abbreviations used are: s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet, br=broad, etc.

Chemical symbols have their usual meanings;

μL (microliter(s)), μg (microgram(s)), M (mol(s) per liter), L(liter(s)), mL (milliliter(s)), g (gram(s)), mg (milligram(s)), mol(moles), mmol (millimoles).

Conditions for Determining HPLC Retention Time:

Method A:

Apparatus: Waters Acquity Ultra Performance LC on TUV Detector and ZQmass spectrometer

Column: Waters ACQUITY C18, 2.1×50 mm, 1.7 micrometer particle

Column Temperature: 60° C.

UV detection: 210 nm scan

MS detection: ESI positive mode

Solvents:

A1: 10 mM ammonium acetate aqueous solution

B1: acetonitrile

TABLE 1 Time(min) A1(%) B1(%) 0 95 5 0.1 95 5 0.8 5 95 1 95 5 run time1.5 min flow 1 ml/min

Method B:

Apparatus: Waters Alliance HPLC system on ZQ mass spectrometer and UVdetector

Column: Waters SunFire C18 2.1×50 mm, 3.5 micrometer particle

Column Temperature: 40° C.

PDA detection: 210-400 nm scan

MS detection: ESI positive mode

Solvents:

A: water

B: acetonitrile

C: 1% (v/v) formic acid aqueous solution

TABLE 2 Time(min) A(%) B(%) C(%) 0 90 5 5 0.5 90 5 5 3.5 0 95 5 4.5 90 55 run time 5 min flow 1 ml/min

Method C:

Apparatus: Waters Acquity Ultra Performance LC on TUV Detector and ZQmass spectrometer

Column: Waters ACQUITY C18, 2.1×100 mm, 1.7 micrometer particle

Column Temperature: 60° C.

UV detection: 210 nm scan

MS detection: ESI positive mode

Solvents:

A1: 10 mM ammonium acetate aqueous solution

B1: acetonitrile

TABLE 3 Time(min) A1(%) B1(%) 0 95 5 0.1 95 5 1.8 5 95 2.3 95 5 run time3 min flow 0.7 ml/min

Method D:

Apparatus: Waters Acquity Ultra Performance LC on TUV Detector and ZQmass spectrometer

Column: Waters ACQUITY C18, 2.1×100 mm, 1.7 micrometer particle

Column Temperature: 60° C.

UV detection: 210 nm scan

MS detection: ESI positive mode

Solvents:

A1: 0.05% aqueous ammonia

B1: acetonitrile

TABLE 4 Time(min) A1(%) B1(%) 0 95 5 0.1 95 5 1.8 5 95 2.3 95 5 run time3 min flow 0.7 ml/min

Method E:

Apparatus: Waters Alliance HPLC system on ZQ mass spectrometer and UVdetector

Column: Waters XBridge C18 2.1×50 mm, 3.5 micrometer particle

Column Temperature: 40° C.

PDA detection: 210-400 nm scan

MS detection: ESI positive mode

Solvents:

A1: water

B1: acetonitrile

C1: 1% aqueous ammonia

TABLE 5 Time(min) A1(%) B1(%) C1(%) 0 90 5 5 0.5 90 5 5 3.5 0 95 5 4.595 5 5 run time 5 min flow 1 ml/min

All of the picolinamide derivatives of the formula (I) can be preparedby the procedures described in the general methods presented above or bythe specific methods described in the Examples section and thePreparations section, or by routine modifications thereof. The presentinvention also encompasses any one or more of these processes forpreparing the picolinamide derivatives of formula (I), in addition toany novel intermediates used therein.

In the following general methods, R¹, R², R³, R⁴, and n are aspreviously defined for picolinamide derivatives of the formula (I)unless otherwise stated.

Example 13-(((R)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1. (R)-tert-butyl2-((2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate

A mixture of tert-butyl(2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (7.38 g,26.4 mmol, Tetrahedron Asymmetry, 1997, 8, 2209-2213),3-hydroxypicolinonitrile (4.76 g, 39.6 mmol), and potassium carbonate(10.95 g, 79.0 mmol) in N,N-dimethylformamide (150 mL) was stirred at100° C. for 6 h. After cooling to room temperature, the mixture waspoured into water, and the aqueous layer was extracted with ethylacetate twice. The combined organic layers were dried over magnesiumsulfate and concentrated in vacuo. The residual oil was purified bysilica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1) togive 3.62 g (45%) of the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ 8.26 (1H, d, J=4.4 Hz), 7.57 (1H, d, J=8.1 Hz), 7.46(1H, dd, J=8.1, 4.4 Hz), 4.30-3.95 (3H, m), 3.48-3.28 (2H, m), 2.19-1.83(4H, m), 1.46 (9H, s).

MS (ESI) m/z: 304 (M+H)⁺.

Step 2. (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate

To a solution of (R)-tert-butyl2-((2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (3.62 g,11.9 mmol, EXAMPLE 1 Step 1) in tert-butanol (110 mL) was addedpotassium hydroxide pellet (10.0 g, 179 mmol) at room temperature. Theresulting mixture was stirred at 80° C. for 0.5 h. After cooling to roomtemperature, the mixture was poured into water, and the aqueous layerwas extracted with ethyl acetate twice. The combined organic layers werewashed with brine, dried over magnesium sulfate, and concentrated invacuo. The residual oil was purified by silica gel column chromatography(dichloromethane to methanol/dichloromethane 1:15) to give 3.43 g (90%)of the title compound as a white amorphous powder.

¹H-NMR (CDCl₃) δ 8.26 (1H, d, J=4.4 Hz), 7.71 (1H, br), 7.56 (1H, d,J=8.1 Hz), 7.40 (1 H, dd, J=8.1, 4.4 Hz), 5.67 (1H, br), 4.30-3.90 (3H,m), 3.49-3.33 (2H, m), 2.23-1.60 (4H, m), 1.46 (9H, s).

MS (ESI) m/z: 322 (M+H)⁺.

Step 3. (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride

A solution of (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (3.43 g,10.7 mmol, EXAMPLE 1 Step 2) in 4.0 M hydrogen chloride in ethyl acetate(100 mL) was stirred at room temperature for 5 h. Diisopropyl ether (150mL) was added to the mixture, and the formed white precipitate wascollected by filtration. The precipitate was dried under reducedpressure to give 2.89 g (92%) of the title compound as a white solid.

¹H-NMR (DMSO-d6) δ 9.60 (1H, br), 9.13 (1H, br), 8.27 (1H, d, J=4.4 Hz),7.97 (1H, br), 7.74 (1H, d, J=8.8 Hz), 7.57 (1H, dd, J=8.8, 4.4 Hz),4.43-4.35 (1H, m), 4.33-4.23 (1H, m), 4.05-3.8 (1H, m), 3.39-3.19 (2H,m), 2.20-1.98 (2H, m), 1.96-1.80 (4H, m).

MS (ESI) m/z: 222 (M+H).

Step 4.3-(((R)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

To an ice-cold solution of cis-4-(trifluoromethyl)cyclohexanecarboxylicacid (267 mg, 1.36 mmol) in dichloromethane (5 mL), oxalyl chloride(0.18 mL, 2.04 mmol) and several drop of N,N-dimethylformamide wereadded. After being stirred at room temperature for 1 h, the mixture wasconcentrated in vacuo to give a waxy solid. The residual solid wasdissolved with dichloromethane (3 mL) and added to the mixture of(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (200 mg, 0.68mmol, EXAMPLE 1 Step 3) and triethylamine (0.48 mL, 3.40 mmol) indichloromethane (5 mL) at 0° C. After being stirred at 0° C. for 2 h,the mixture was dissolved with ethyl acetate and 2 N hydrochloric acid.The aqueous layer was washed with ethyl acetate, and basified with aq.ammonia. The mixture was extracted with ethyl acetate twice, and washedwith brine. The combined extracts were dried over sodium sulfate andconcentrated in vacuo to give an amber oil. The residual oil waspurified by preparative TLC (methanol/dichloromethane 1:10) to afford160 mg of the title compound as a colorless viscous oil.

¹H-NMR (CDCl₃) δ 8.20 (1H, dd, J=4.4, 1.5 Hz), 7.61 (1H, brs), 7.55 (1H,dd, J=8.8, 1.5 Hz), 7.41 (1H, dd, J=8.1, 4.4 Hz), 5.56 (1H, brs), 4.45(1H, m), 4.33 (1H, dd, J=9.5, 5.9 Hz), 4.21 (1H, dd, J=10.3, 2.9 Hz),3.7-3.6 (1H, m), 3.6-3.4 (1H, m), 2.63 (1H, m), 2.4-2.1 (2H, m), 2.2-1.8(6H, m), 1.8-1.5 (5H, m).

MS (ESI) m/z: 400 (M+H)⁺.

HPLC Retention time: 0.66 min (Method A).

Example 23-(((S)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inEXAMPLE 1 using (S)-tert-butyl

2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (TetrahedronAsymmetry, 1997, 8, 2209-2213) instead of (R)-tert-butyl2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ 8.20 (1H, dd, J=4.4, 1.5 Hz), 7.61 (1H, brs), 7.55 (1H,dd J=8.8, 1.5 Hz), 7.41 (1H, dd, J=8.8, 4.4 Hz), 5.62 (1H, brs), 4.45(1H, m), 4.32 (1H, dd, J=9.5, 5.9 Hz), 4.21 (1H, dd, J=9.5, 2.9 Hz),3.7-3.6 (1H, m), 3.50 (1H, m), 2.63 (1H, m), 2.4-2.2 (2 H, m), 2.2-1.8(6H, m), 1.8-1.4 (5H, m).

MS (ESI) m/z: 400 (M+H)⁺.

HPLC Retention time: 0.66 min (Method A).

Example 3(R)-3-((1-(1H-indole-2-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1.(R)-3-((1-(1H-indole-2-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide

A mixture of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride(25 mg, 0.085 mmol, EXAMPLE 1 Step 3), indole-2-carboxylic acid (15 mg,0.093 mmol), triethylamine (0.060 mL, 0.43 mmol), andN,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate (HBTU) (48 mg, 0.13 mmol) in acetonitrile (1 mL) wasstirred at room temperature for 4 h. The mixture was poured into water,and the aqueous layer was extracted with dichloromethane twice. Thecombined organic layers were dried over magnesium sulfate andconcentrated in vacuo. The residual solid was washed with methanol togive 22 mg (71%) of the title compound as a white solid.

¹H-NMR (DMSO-d6) δ 11.60 (1H, s), 8.11 (1H, d, J=4.4 Hz), 7.80-7.60 (3H,m), 7.51-7.37 (3H, m), 7.19 (1H, t, J=8.0 Hz), 7.04 (1H, t, J=7.3 Hz),6.98 (1H, br), 4.62-4.52 (1H, m), 4.33-4.15 (2H, m), 4.00-3.83 (2H, m),2.32-1.90 (4H, m).

MS (ESI) m/z: 365 (M+H)⁺, 363 (M−H)⁻.

Example 4-28

The following examples, EXAMPLE 4-28, were prepared according to theprocedure similar to that described in the Step 1 of the EXAMPLE 3,using the appropriate precursor instead of indole-2-carboxylic acid. Inthe following examples, products of Example 4-28 were purified bypreparative HPLC.

TABLE 6-1 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R³Chemical Name Method (min.) (M + H)+ 4

(R)-3-((1-(1-methylcyclohexane- carbonyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.43 346 5

(R)-3-((1-(4-(trifluoromethyl) benzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.38 394 6

(R)-3-((1-(4-chloro-3-fluorobenzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.35 378 7

(R)-3-((1-(3-chloro-4-fluorobenzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.33 378 8

(R)-3-((1-(3-chloro-2-fluorobenzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.30 378 9

(R)-3-((1-(4-chloro-2-fluorobenzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.32 378 10

(R)-3-((1-(3-fluoro-4-methylbenzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 2.31 358 11

(R)-3-((1-(2-(2,4-difluorophenyl) acetyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.29 376 12

(R)-3-((1-(2-(4-(trifluoromethyl) phenyl)acetyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.42 408

TABLE 6-2 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R³Chemical Name Method (min.) (M + H)+ 13

(R)-3-((1-(3-p-tolylpropanoyl) pyrrolidin-2-yl)methoxy)picolinamideMethod D 1.40 368 14

(R)-3-((1-(cyclohexanecarbonyl) pyrrolidin-2-yl)methoxy)picolinamideMethod C 1.30 332 15

(R)-3-((1-(1-methyl-5-(trifluoro- methyl)-1H-pyrazole-3-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.29 398 16

(R)-3-((1-(6-tert-butylnicotinoyl) pyrrolidin-2-yl)methoxy)picolinamideMethod C 1.33 383 17

(R)-3-((1-(5-tert-butylisoxazole- 3-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.42 373 18

(R)-3-((1-(2-(4-(trifluoromethyl) phenoxy)acetyl)pyrroilidin-2-yl)methoxy)picolinamide Method C 1.43 424 19

(R)-3-((1-(4-fluoro-3-methybenzoyl) pyrrolidin-2-yl)methoxy)picolinamideMethod C 1.30 358 20

(R)-3-((1-(1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl)pyrrolidin-2-yl) methoxy)picolinamide Method C1.25 415 21

(R)-3-((1-(4-(2,2,2-trifluoroethoxy) benzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.38 424

TABLE 6-3 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R³Chemical Name Method (min.) (M + H)+ 22

(R)-3-((1-(4,4-difluoro- cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.23 368 23

(R)-3-((1-(5-(trifluoromethyl) picolinoyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.28 395 24

(R)-3-((1-(6-trifluoromethyl) nicotinoyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.24 395 25

(R)-3-((1-(4-(trifluoromethoxy) benzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method D 1.42 410 26

(R)-3-((1-(1-methyl-1H-indole- 2-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.38 379 27

(R)-3-((1-(1H-indole-3-carbonyl) pyrrolidin-2-yl)methoxy) picolinamideMethod C 1.16 365 28

(R)-3-((1-(1-methyl-1H-indole- 3-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.27 379

Example 295-chloro-3-(((R)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1. (R)-tert-butyl2-((5-chloropyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate

To a stirred solution of 5-chloropyridin-3-ol (1.46 g, 11.28 mmol),(R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.27 g, 11.28mmol), and triphenylphosphine (2.96 g, 11.28 mmol) in THF (50 mL) wasadded di-tert-butyl azodicarboxylate (DTAD) (2.60 g, 11.28 mmol) at 0°C. The mixture was stirred at 0° C. for 1 h and warmed to roomtemperature. After being stirred at room temperature for 2 days, themixture was concentrated in vacuo to afford a dark brown viscous oil.The residual oil was crystallized from isopropyl ether (IPE)-hexane, andformed precipitate was removed by filtration. The filtrate wasconcentrated in vacuo to afford a dark brown oil. The residual oil waspurified by silica gel column chromatography (ethyl acetate/hexane 1:9to 1:5) to afford crude 5.15 g (quant.) of the title compound as acolorless gel. The crude title compound was used for the next stepwithout further purification.

¹H-NMR (CDCl₃) δ 8.22 (2H, br), 7.32 (1H, br), 4.2-3.8 (3H, m), 3.36(2H, br), 2.1-1.8 (4H, m), 1.48 (9H, s).

MS (ESI) m/z: 313 (M+H)⁺.

Step 2.(R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-5-chloropyridine1-oxide

To a stirred mixture of crude (R)-tert-butyl2-((5-chloropyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (5.15 g,Ca. 11.28 mmol, EXAMPLE 29 Step 1) and sodium bicarbonate (2.77 g, 32.9mmol) in dichloromethane was added m-chloroperbenzoic acid (mCPBA) (4.26g, 24.7 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, andthe mixture was warmed to room temperature during 30 min period. Afterbeing stirred at room temperature for 6 h, water was added to themixture. The mixture was extracted with dichloromethane twice and washedwith aq. sodium thiosulfate and brine. The extracts were combined anddried over sodium sulfate and concentrated in vacuo to afford an oil.The residual oil was purified by silica gel column chromatography (ethylacetate/hexane 7:3 to ethyl acetate) to afford 2.709 g (73% from5-chloropyridin-3-ol) of the title compound as a colorless viscous oil.

¹H-NMR (CDCl₃) δ 7.90 (2H, brs), 7.0-6.9 (1H, br), 4.2-3.8 (3H, m), 3.34(2H, br), 2.2-1.8 (4H, m), 1.47 (9H, s).

MS (ESI) m/z: 329 (M+H)⁺.

Step 3. (R)-tert-butyl2-((5-chloro-2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate

To a stirred solution of(R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-5-chloropyridine1-oxide (610 mg, 1.855 mmol, EXAMPLE 29 Step 2) and triethylamine (1.56mL, 11.13 mmol) in acetonitrile was added trimethylsilyl cyanide (TMSCN)(1.24 mL, 9.28 mmol) at ambient temperature and the mixture was heatedat 80° C. After being stirred at 80° C. for 15 h, the mixture was cooledto room temperature. 1.24 mL of TMSCN (9.28 mmol) and 1.56 mL oftriethylamine (11.13 mmol) were added to the mixture and the mixture washeated at 80° C. further 6 h. After cooling to room temperature, themixture was concentrated in vacuo to give a dark brown oil. The residualoil was dissolved with ethyl acetate and 2 N aq. sodium hydroxide. Themixture was extracted with ethyl acetate twice and washed with water, 2N hydrochloric acid, and brine. The extracts were combined and driedover sodium sulfate and concentrated in vacuo to afford an oil. Theresidual oil was purified by silica gel column chromatography (hexane toethyl acetate/hexane 1:4) to afford 364 mg (58%) of the title compoundas a waxy solid.

¹H-NMR (CDCl₃) δ 8.23 (1H, brs), 7.57 (0.7H, brs), 7.39 (0.3H, brs),3.9-4.4 (3H, m), 3.40 (2H, br), 2.10 (3H, brs) 2.0-1.8 (1H, br), 1.46(9H, s).

MS (ESI) m/z: 338 (M+H)⁺.

Step 4. (R)-tert-butyl2-((2-carbamoyl-5-chloropyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared according to the procedure described inStep 2 of EXAMPLE 1 using (R)-tert-butyl2-((5-chloro-2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate(EXAMPLE 29 Step 3) instead of (R)-tert-butyl2-((2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ 8.22 (1H, brs), 7.7-7.4 (2H, brm), 5.79 (1H, br),4.3-3.9 (3H, m), 3.39 (2 H, br), 2.2-1.7 (4H, m), 1.46 (9H, s).

MS (ESI) m/z: 356 (M+H)⁺.

Step 5. (R)-5-chloro-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using (R)-tert-butyl2-((2-carbamoyl-5-chloropyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate(EXAMPLE 29 Step 4) instead of (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

¹H-NMR (DMSO-d6) δ 9.66 (1H, br), 9.19 (1H, br), 8.28 (1H, d, J=1.6 Hz),8.02 (1H, brs), 7.89 (1H, d, J=1.7 Hz), 7.68 (1H, brs), 4.5-4.2 (2H, m),4.2-3.8 (2H, m), 3.22 (2H, br), 2.2-1.7 (4H, m).

MS (ESI) m/z: 256 (M+H)⁺.

Step 6.5-chloro-3-(((R)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 3 using(R)-5-chloro-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride(EXAMPLE 29 Step 5) and cis-4-(trifluoromethyl)cyclohexanecarboxylicacid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride and indole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ 8.15 (1H, d, J=1.5 Hz), 7.51 (2H, brd, J=1.2 Hz), 5.50(1H, br), 4.5-4.0 (1H, m), 4.37 (1H, dd, J=9.5, 5.1 Hz), 4.15 (1H, dd,J=9.5, 2.9 Hz), 3.69 (1H, m), 3.52 (1H, m), 2.64 (1H, m), 2.4-2.2 (1H,m), 2.2-1.8 (7H, m), 1.8-1.5 (5H, m).

MS (ESI) m/z: 434 (M+H)⁺.

HPLC Retention time: 0.73 min (Method A).

Example 305-chloro-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 3 using(R)-5-chloro-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride(EXAMPLE 29 Step 5) and trans-4-(trifluoromethyl)cyclohexanecarboxylicacid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride and indole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ 8.14 (1H, d, J=1.2 Hz), 7.53 (2H, brd, J=1.5 Hz), 5.50(1H, br), 4.45 (1H, m), 4.32 (1H, dd, J=9.5, 5.1 Hz), 4.17 (1H, dd,J=9.5, 3.7 Hz), 3.70 (1H, m), 3.54 (1 H, m), 2.4-2.2 (2H, m), 2.2-1.8(8H, m), 1.6-1.2 (4H, m).

MS (ESI) m/z: 434 (M+H)⁺.

Example 315-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1. [(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 3 using (R)-pyrrolidin-2-ylmethanol andtrans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride andindole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ 5.03 (1H, dd, J=8.1, 2.2 Hz), 4.3-4.2 (1H, m), 3.7-3.5(4H, m), 2.37 (1 H, m), 2.2-1.8 (8H, m), 1.8-1.5 (3H, m), 1.5-1.2 (2H,m).

MS (ESI) m/z: 280 (M+H)⁺.

Step 2. ethyl 3-hydroxy-5-methoxypicolinate

3-hydroxy-5-methoxypicolinic acid (200 mg, 1.18 mmol) was dissolved inethanol (10 mL). To the mixture was added one drop of sulfuric acid. Themixture was refluxed with stirring for 3 days. After cooling to roomtemperature, the mixture was concentrated in vacuo to afford an oil. Theresidual oil was dissolved in ethyl acetate and washed with aq. sodiumbicarbonate and brine. The extract was dried over sodium sulfate andconcentrated in vacuo to afford an oil. The residual oil was purified bysilica gel column chromatography (ethyl acetate/hexane 1:3 to 1:1) toafford 178 mg (76%) of the title compound as a white solid.

¹H-NMR (CDCl₃) δ 11.00 (1H, s), 7.99 (1H, d, J=2.2 Hz), 6.77 (1H, d,J=2.2 Hz), 4.50 (2 H, q, J=6.6 Hz), 3.88 (3H, s), 1.47 (3H, t, J=6.6Hz).

MS (ESI) m/z: 198 (M+H)⁺, 196 (M−H)⁻.

Step 3. ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using ethyl 3-hydroxy-5-methoxypicolinate (EXAMPLE31 Step 2) and[(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol(EXAMPLE 31 Step 1) instead of 5-chloropyridin-3-ol and(R)-pyrrolidin-2-ylmethanol.

¹H-NMR (CDCl₃) δ 7.97 (1H, d, J=2.2 Hz), 7.09 (1H, d, J=2.2 Hz), 4.42(1H, m), 4.40 (2 H, q, J=7.3 Hz), 4.30-4.15 (2H, m), 3.92 (3H, s),3.70-3.45 (2H, m), 2.50-1.75 (10H, m), 1.70-1.25 (4H, m), 1.41 (3H, t,J=6.6 Hz).

MS (ESI) m/z: 459 (M+H)⁺.

Step 4.5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid

To a solution of5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate (170 mg, 0.37 mmol, EXAMPLE 31 Step 3) intetrahydrofuran was added 2 N aq. sodium hydroxide (0.5 mL, 1.00 mmol)at room temperature. After being stirred at room temperature for 24 h,water and diethylether were added to the mixture. The aqueous layer waswashed with diethylether and acidified with 2 N hydrochloric acid. Theaqueous layer was extracted with ethyl acetate. The extract was driedover sodium sulfate and concentrated in vacuo to afford 151 mg (95%) ofthe title compound as an oil. The residual oil was used for the nextstep without further purification.

MS (ESI) m/z: 431 (M+H)⁺, 429 (M−H)⁻.

Step 5.5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

To a solution of5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (150 mg, 0.35 mmol, EXAMPLE 31 Step 4) and ammonium chloride (56mg, 1.05 mmol) in dichloromethane (5 mL) were added1-ethyl-3-((3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (100mg, 0.52 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (53 mg, 0.35 mmol)and triethylamine (176 mg, 1.74 mmol) respectively. After being stirredat room temperature for 24 h, water was added to the mixture. Themixture was extracted with dichloromethane, and the extract was driedover sodium sulfate and concentrated in vacuo to afford an oil. Theresidual oil was purified by NH gel column chromatography(methanol/dichloromethane 1:30) followed by preparative high pressureliquid chromatography (prep. HPLC) (acetonitrile/0.01% aq. ammonia 96:4to 4:96) to afford 75 mg (50%) of the title compound as an amorphouspowder.

¹H-NMR (CDCl₃) δ 7.90 (1H, d, J=2.2 Hz), 7.53 (1H, brs), 7.11 (1H, d,J=2.2 Hz), 5.40 (1 H, brs), 4.45 (1H, m), 4.26 (1H, dd, J=10.3, 5.9 Hz),4.20 (1H, dd, J=10.3, 3.7 Hz), 3.93 (3H, s), 3.69 (1H, m), 3.52 (1H, m),2.45-2.15 (3H, m), 2.15-1.75 (7H, m), 1.65-1.20 (4H, m).

MS (ESI) m/z: 430 (M+H)⁺, 428 (M−H)⁻.

Example 325-(trifluoromethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1.3-(trifluoromethyl)-5-{[(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methoxy}pyridine

NaH (60% oil dispersant, 11 mg, 0.27 mmol) was placed on the reactiontube, and a solution of[(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol(68 mg, 0.24 mmol, EXAMPLE 31 Step 1) in DMSO (2.0 mL) was added atambient temperature. After being stirred for 15 min at room temperature,3-bromo-5-(trifluoromethyl)pyridine (50 mg, 0.22 mmol) was added to themixture at ambient temperature. The mixture was heated stepwise withcontinuous stirring, at room temperature for 19 h, at 50° C. for 3 h, at80° C. for 15 h, and at 100° C. for 15 h. After cooling to roomtemperature, water was added to the mixture. The mixture was extractedwith ethyl acetate twice and washed with brine. The extracts werecombined and dried over sodium sulfate and concentrated in vacuo to givean oil. The residual oil was purified by silica gel preparative thinlayer chromatography (TLC) (ethyl acetate/hexane 3:2) to afford 40 mg(43%) of the title compound as a colorless viscous oil.

¹H-NMR (CDCl₃) δ 8.48 (2H, brs), 7.44 (1H, brs), 4.5-4.3 (1H, m), 4.24(1H, dd, J=8.8, 2.9 Hz), 4.14 (1H, dd, J=8.8, 6.6 Hz), 3.56 (2H, m),2.36 (1H, tt, J=11.7, 3.7 Hz), 2.2-1.8 (8H, m), 1.7-1.4 (3H, m), 1.4-1.2(2H, m).

MS (ESI) m/z: 425 (M+H)⁺.

Step 2.3-(trifluoromethyl)-5-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)pyridine1-oxide

The title compound was prepared according to the procedure described inStep 2 of EXAMPLE 29 using3-(trifluoromethyl)-5-{[(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methoxy}pyridine(EXAMPLE 32 Step 1) instead of (R)-tert-butyl2-((5-chloropyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ 8.12 (2H, s), 7.13 (1H, s), 4.40 (1H, m), 4.24 (1H, dd,J=9.2, 2.6 Hz), 4.09 (1H, dd, J=9.2, 7.3 Hz), 3.55 (2H, m), 2.35 (1H,tt, J=11.9, 3.3 Hz), 2.2-2.0 (7H, m), 2.0-1.7 (2H, m), 1.7-1.4 (2H, m),1.4-1.2 (2H, m).

MS (ESI) m/z: 441 (M+H)⁺.

Step 3.5-(trifluoromethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinonitrile

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 29 using3-(trifluoromethyl)-5-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)pyridine1-oxide (EXAMPLE 32 Step 2) instead of(R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-5-chloropyridine1-oxide.

¹H-NMR (CDCl₃) δ 8.53 (1H, s), 7.7 (1H, s), 4.50 (1H, dd, J=8.8, 5.1Hz), 4.44 (1H, m), 4.27 (1H, dd, J=8.8, 2.2 Hz), 3.70 (1H, m), 3.59 (1H,m), 2.5-2.2 (2H, m), 2.2-2.0 (6H, m), 2.0-1.8 (2H, m), 1.7-1.2 (4H, m).

MS (ESI) m/z: 450 (M+H)⁺.

Step 4.5-(trifluoromethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 2 of EXAMPLE 1 using5-(trifluoromethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinonitrile(EXAMPLE 32 Step 3) instead of (R)-tert-butyl2-((2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate withpreparative HPLC purification.

¹H-NMR (CDCl₃) δ 8.44 (1H, s), 7.67 (1H, s), 7.56 (1H, brs), 5.61 (1H,brs), 4.49 (1H, m), 4.37 (1H, dd, J=9.5, 4.4 Hz), 4.21 (1H, dd, J=9.5,3.6 Hz), 3.72 (1H, m), 3.56 (1H, m), 2.5-2.3 (2H, m), 2.2-1.8 (8H, m),1.7-1.2 (4H, m).

MS (ESI) m/z: 468 (M+H)⁺, 466 (M−H)⁻.

HPLC Retention time: 2.80 min (Method B).

Example 33N-(2-hydroxyethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1. (R)-ethyl3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using ethyl 3-hydroxypicolinate instead of5-chloropyridin-3-ol.

MS (ESI) m/z: 351 (M+H)⁺.

Step 2. (R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using (R)-ethyl3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate (EXAMPLE33 Step 1) in stead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

MS (ESI) m/z: 323 (M+H)⁺, 321 (M−H)⁻.

Step 3. (R)-tert-butyl2-((2-(2-hydroxyethylcarbamoyl)pyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 from(R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid(EXAMPLE 33 Step 2) using ethanolamine instead of ammonium chloride.

¹H-NMR (CDCl₃) δ 8.30-7.90 (2H, m), 7.70-7.25 (2H, m), 4.40-3.75 (5H,m), 3.70-3.50 (2H, m), 3.45-3.25 (2H, m), 2.20-1.70 (4H, m), 1.45 (9H,s). A signal due to OH was not observed.

MS (ESI) m/z: 366 (M+H)⁺, 364 (M−H)⁻.

Step 4. (R)—N-(2-hydroxyethyl)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride

(R)-tert-butyl

2-((2-(2-Hydroxyethylcarbamoyl)Pyridin-3-Yloxy)Methyl)Pyrrolidine-1-Carboxylate(330 mg, 0.90 mmol, EXAMPLE 33 Step 3) was dissolved in 10% hydrogenchloride in methanol (8 mL) at room temperature. After being stirred atroom temperature for 4 days, the volatile was evaporated to afford 304mg (quant.) of the title compound that was used directly in the nextstep without further purification.

¹H-NMR (DMSO-d6) δ 9.74 (1H, brs), 9.33 (1H, brs), 8.68 (1H, m), 8.31(1H, d, J=5.1 Hz), 7.87 (1H, d, J=8.0 Hz), 7.68 (1H, dd, J=8.8, 4.4 Hz),4.46 (1H, m), 4.33 (1H, m), 3.99 (1 H, brs), 3.60-3.48 (2H, m),3.45-3.30 (2H, m), 3.30-3.15 (2H, m), 2.25-1.75 (6H, m).

MS (ESI) m/z: 266 (M+H)⁺.

Step 5.N-(2-hydroxyethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using(R)—N-(2-hydroxyethyl)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride (EXAMPLE 33 Step 4) andtrans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of ammoniumchloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.

¹H-NMR (CDCl₃) δ 8.18 (1H, d, J=4.4 Hz), 8.14 (1H, brs), 7.59 (1H, d,J=8.8 Hz), 7.38 (1 H, dd, J=8.8, 4.4 Hz), 4.46 (1H, m), 4.25 (1H, dd,J=10.2, 3.7 Hz), 4.17 (1H, dd, J=10.2, 5.9 Hz), 3.84 (2H, brs),3.75-3.45 (4H, m), 3.35 (1H, brs), 2.45-2.15 (2H, m), 2.15-1.70 (8 H,m), 1.65-1.20 (4H, m).

MS (ESI) m/z: 444 (M+H)⁺, 442 (M−H)⁻.

HPLC Retention time: 0.65 min (Method A).

Example 34N-(4H-1,2,4-triazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1. (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinatebis(trifluoroactetic acid) salt

To a solution of (R)-ethyl3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate (1.00 g,285 mmol, EXAMPLE 33 Step 1) in dichloromethane (10 mL) was addedtrifluoroacetic acid (3 mL) at room temperature. After being stirred atroom temperature for 8 h, the volatile was evaporated to afford 1.36 g(quant.) of the title compound that was used directly in the next stepwithout further purification.

MS (ESI) m/z: 251 (M+H)⁺.

Step 2. ethyl3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using (R)-ethyl3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroactetic acid) salt(EXAMPLE 34 Step 1) and trans-4-(trifluoromethyl)cyclohexanecarboxylicacid instead of ammonium chloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.

¹H-NMR (CDCl₃) δ 8.25 (1H, dd, J=4.4, 1.5 Hz), 7.56 (1H, dd, J=8.8, 1.5Hz), 7.38 (1H, dd, J=8.8, 4.4 Hz), 4.43 (2H, q, J=7.3 Hz), 4.43 (1H, m),4.30-4.18 (2H, m), 3.70-3.40 (2 H, m), 2.50-1.75 (10H, m), 1.63-1.20(4H, m), 1.42 (3H, t, J=7.3 Hz).

MS (ESI) m/z: 429 (M+H)⁺.

Step 3.3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using ethyl3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 34 Step 2) instead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.

¹H-NMR (CDCl₃) δ 8.18 (1H, d, J=4.4 Hz), 7.70 (1H, d, J=8.8 Hz), 7.56(1H, dd, J=8.8, 4.4 Hz), 4.55-4.35 (2H, m), 4.22 (1H, m), 3.77 (1H, m),3.54 (1H, m), 2.50-2.30 (2H, m), 2.22 (1H, m), 2.15-1.80 (6H, m),1.70-1.20 (5H, m). A signal due to COOH was not observed.

MS (ESI) m/z: 401 (M+H)⁺, 399 (M−H)⁻.

Step 4.N-(4H-1,2,4-triazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

To a solution of3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (30 mg, 0.08 mmol, EXAMPLE 34 Step 3) in dichloromethane (1 mL)were added oxalyl chloride (33 microL, 0.38 mmol) and a catalytic amountof N,N-dimethylformamide at room temperature. After being stirred atroom temperature for 30 min, the volatile was removed under reducedpressure. The resulting residue was dissolved in toluene (1 mL).Triethyl amine (10 microL, 0.08 mmol) and 4H-1,2,4-triazol-3-amine (8mg, 0.09 mmol) were added to the mixture. After being refluxed for 15 h,the volatile was removed by evaporation. The residual material wasdissolved in dichloromethane. The organic layer was washed with aq.sodium bicarbonate and concentrated in vacuo to afford the titlecompound as a brown oil. The crude product was purified by preparativeHPLC.

MS (ESI) m/z: 467 (M+H)⁺, 465 (M−H)⁻.

HPLC Retention time: 1.41 min (Method C).

Example 35-59

The following examples, EXAMPLE 35-59, were prepared according to thefollowing described procedure, utilizing the carboxylic acid,3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 34 Step 3) with preparative HPLC purification.

The following examples, EXAMPLE 35-44, were prepared according to theprocedure similar to that described in the Step 5 of the EXAMPLE 31,using the appropriate precursor of amine, R²—NH₂.

The following examples, EXAMPLE 45-50, were prepared according to theprocedure similar to that described in the Step 1 of the EXAMPLE 3,using the appropriate precursor of amine, R²—NH₂.

The following examples, EXAMPLE 51-59, were prepared according to theprocedure similar to that described in the Step 4 of the EXAMPLE 1,using the appropriate precursor of amine, R²—NH₂.

TABLE 7-1 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R²Chemical Name Method (min.) (M + H)+ 35

methyl 2-(3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl) methoxy)picolinamido)acetate MethodC 1.55 472 36

N-(2-morpholinoethyl)-3-(((R)-1- (trans-4-(trifluoromethyl)cyclohexane-carbonyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.47 513 37

N-(2-methoxyethyl)-3-(((R)-1-(trans- 4-(trifluoromethyl)cyclohexane-carbonyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.53 458 38

N-(2-(pyrrolidin-1-yl)ethyl)-3-(((R)-1- (trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 2-yl)methoxy)picolinamide Method C 1.39497 39

N-((1-hydroxycyclohexyl)methyl)- 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl) methoxy)picolinamide Method C 1.66512 40

N-(pyridin-2-ylmethyl)-3-(((R)-1- (trans-4-(trifluoromethyl)cyclohexane-carbonyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.55 491

TABLE 7-2 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R²Chemical Name Method (min.) (M + H)+ 41

N-benzyl-3-(((R)-1-(trans-4- (trifluoromethyl)cyclohexane-carbonyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.74 490 42

N-(((R)-2-hydroxy-1-phenylethyl)- 3-(((R)-1-(trans-4-(trifluoro-methyl)cyclohexanecarbonyl) pyrrolidin-2-yl)methoxy) picolinamide MethodB 3.37 520 43

N-((S)-2-hydroxy-1-phenylethyl)- 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 2-yl)methoxy)picolinamide Method B 3.37520 44

N-phenyl-3-(((R)-1-(trans-4- (trifluoromethyl)cyclohexane-carbonyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.80 476 45

N-(4-methyloxazol-2-yl)-3-(((R)- 1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2- yl)methoxy)picolinamide Method C 1.60481 46

N-(oxazol-2-yl)-3-(((R)-1-(trans- 4-(trifluoromethyl)cyclohexane-carbonyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.54 467

TABLE 7-3 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R²Chemical Name Method (min.) (M + H)+ 47

N-(1,2,4-thiadiazol-5-yl)-3-(((R)- 1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2- yl)methoxy)picolinamide Method C 1.68484 48

N-((tetrahydro-2H-pyran-4-yl) methyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexane- carbonyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.54 498 49

N-(tetrahydro-2H-pyran-4-yl)- 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2- yl)methoxy)picolinamide Method C 1.51484 50

N-(1H-1,2,4-triazol-5-yl)-3-(((R)- 1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2- yl)methoxy)picolinamide Method C 1.35481 51

N-(isoxazol-5-yl)-3-(((R)-1-(trans- 4-(trifluoromethyl)cyclohexane-carbonyl)pyrrolidin-2-yl)methoxy) picolinamide Method B 2.84 467 52

N-(1,5-dimethyl-1H-pyrazol-3-yl)- 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 2-yl)methoxy)picolinamide Method C 1.60494 53

N-(1-methyl-1H-pyrazol-3-yl)-3- (((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 2-yl)methoxy)picolinamide Method C 1.54480

TABLE 7-4 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R²Chemical Name Method (min.) (M + H)+ 54

N-(isoxazol-3-yl)-3-(((R)-1- (trans-4-(trifluoromethyl)cyclo-hexanecarbonyl)pyrrolidin-2-yl) methoxy)picolinamide Method C 1.65 46755

N-(1-isopropyl-1H-pyrazol-5-yl)- 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 2-yl)methoxy)picolinamide Method C 1.66508 56

N-(pyrimidin-4-yl)-3-(((R)-1- (trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 2-yl)methoxy)picolinamide Method E 2.60478 57

N-(3-methylisoxazol-5-yl)-3- (((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 2-yl)methoxy)picolinamide Method C 1.71481 58

N-(5-methylisoxazol-3-yl)-3- (((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 2-yl)methoxy)picolinamide Method C 1.71481 59

N-(1-benzyl-1H-pyrazol-3-yl)-3- (((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2- yl)methoxy)picolinamide Method C 1.80556

Example 60N-(1-methyl-1H-pyrazol-3-yl)-3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1.[(2S)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 31 using (S)-pyrrolidin-2-ylmethanol instead of(R)-pyrrolidin-2-ylmethanol.

¹H-NMR (CDCl₃) δ 5.04 (1H, dd, J=6.7, 2.2 Hz), 4.24 (1H, m), 3.69-3.40(4H, m), 2.37 (1 H, tt, J=11.7, 2.9 Hz), 1.33-2.17 (13H, m).

MS (ESI) m/z: 280 (M+H)⁺.

Step 2. ethyl3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using[(2S)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol(EXAMPLE 60 Step 1) and ethyl 3-hydroxypicolinate instead of(R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate and5-chloropyridin-3-ol.

MS (ESI) m/z: 429 (M+H)⁺.

Step 3.3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using ethyl3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 60 Step 2) instead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

¹H-NMR (CDCl₃) δ 8.17 (1H, d, J=4.4 Hz), 7.70 (1H, d, J=8.8 Hz), 7.55(1H, dd, J=8.8, 4.4 Hz), 4.47-4.38 (2H, m), 4.23 (1H, m), 3.77 (1H, m),3.54 (1H, m), 2.50-2.30 (2H, m), 2.22 (1H, m), 2.10-1.80 (6H, m),1.70-1.25 (5H, m). A signal due to COOH was not observed.

MS (ESI) m/z: 401 (M+H)⁺, 399 (M−H)⁻.

Step 4.N-(1-methyl-1H-pyrazol-3-yl)-3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 using3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (Example 60 step 3) and 1-methyl-1H-pyrazol-3-amine instead ofcis-4-(trifluoromethyl)cyclohexanecarboxylic acid and(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride withpreparative HPLC purification.

MS (ESI) m/z: 480 (M+H)⁺.

HPLC Retention time: 1.56 min (Method C).

Example 61N-(oxazol-2-yl)-3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 1 of Example 3 using3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (Example 60 step 3) and oxazol-2-amine instead ofindole-2-carboxylic acid and (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride with prepataive HPLC purification.

MS (ESI) m/z: 467 (M+H)⁺, 465 (M−H)⁺.

HPLC Retention time: 1.54 min (Method C).

Example 62N-(oxazol-2-yl)-3-(((S)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inEXAMPLE 61 using cis-4-(trifluoromethyl)cyclohexanecarboxylic acidinstead of trans-4-(trifluoromethyl)cyclohexanecarboxylic acid withpreparative HPLC purification.

MS (ESI) m/z: 467 (M+H)⁺, 465 (M−H)⁺.

HPLC Retention time: 1.55 min (Method C).

Example 63N-(oxazol-2-yl)-3-(((R)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inEXAMPLE 46 using cis-4-(trifluoromethyl)cyclohexanecarboxylic acidinstead of trans-4-(trifluoromethyl)cyclohexanecarboxylic acid withpreparative HPLC purification.

MS (ESI) m/z: 467 (M+H)⁺, 465 (M−H)⁺.

HPLC Retention time: 1.55 min (Method C).

Example 64(R)-3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)-N-(oxazol-2-yl)picolinamide

Step 1. (R)-tert-butyl2-((2-(oxazol-2-ylcarbamoyl)pyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using(R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid(EXAMPLE 33 Step 2) and oxazol-2-amine instead of5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid and ammonium chloride.

¹H-NMR (CDCl₃) δ10.8 (1H, brs), 8.24 (1H, s), 7.59 (1H, m), 7.53-7.40(2H, m), 7.09 (1H, s), 4.45-3.80 (3H, m), 3.40 (2H, s), 2.45-1.70 (4H,m), 1.44 (9H, s).

MS (ESI) m/z: 389 (M+H)⁺, 387 (M−H)⁻.

Step 2. (R)—N-(oxazol-2-yl)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 33 using (R)-tert-butyl2-((2-(oxazol-2-ylcarbamoyl)pyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate(EXAMPLE 64 Step 1) instead of (R)-tert-butyl2-((2-(2-hydroxyethylcarbamoyl)pyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

¹H-NMR (DMSO-d6) δ 9.79 (1H, brs), 9.24 (1H, brs), 8.29 (1H, d, J=4.4Hz), 7.97 (1H, s), 7.75 (1H, d, J=8.1 Hz), 7.63 (1H, dd, J=8.8, 4.4 Hz),7.20 (1H, s), 4.50-4.25 (2H, m), 3.96 (1H, m), 3.25-3.10 (2H, m),2.25-1.75 (4H, m).

MS (ESI) m/z: 289 (M+H)⁺.

Step 3.(R)-3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)-N-(oxazol-2-yl)picolinamide

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using(R)—N-(oxazol-2-yl)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride (EXAMPLE 64 Step 2) and 2-(4,4-difluorocyclohexyl)aceticacid instead of ammonium chloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid with preparative HPLC purification.

MS (ESI) m/z: 449 (M+H)⁺, 447 (M−H)⁻.

HPLC Retention time: 2.45 min (Method B).

Example 65(R)-3-((1-(5-cyclopropylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)-N-(oxazol-3-yl)picolinamide

Step 1. (R)-ethyl3-((1-(5-cyclopropylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using (R)-ethyl3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifuluoroacetic acid) salt(EXAMPLE 34 Step 1) and 5-cyclopropylisoxazole-3-carboxylic acid insteadof ammonium chloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.

MS (ESI) m/z: 386 (M+H)⁺.

Step 2.

(R)-3-((1-(5-cyclopropylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using (R)-ethyl3-((1-(5-cyclopropylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 65 Step 1) instead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

MS (ESI) m/z: 358 (M+H)⁺, 356 (M−H)⁻.

Step 3.(R)-3-((1-(5-cyclopropylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 1 using(R)-3-((1-(5-cyclopropylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 65 Step 2) and isoxazol-3-amine instead ofcis-4-(trifluoromethyl)cyclohexanecarboxylic acid and(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride withpreparative HPLC purification.

MS (ESI) m/z: 424 (M+H)⁺, 422 (M−H)⁻.

HPLC Retention time: 1.52 min (Method C).

Example 66(R)-3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide

Step 1. (R)-ethyl3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using (R)-ethyl3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifuluoroacetic acid) salt(EXAMPLE 34 Step 1) and 2-(4,4-difluorocyclohexyl)acetic acid instead ofammonium chloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.

¹H-NMR (CDCl₃) δ 8.25 (1H, d, J=5.1 Hz), 7.54 (1H, d, J=8.8 Hz), 7.38(1H, dd, J=8.8, 5.1 Hz), 4.43 (2H, q, J=7.3 Hz), 4.24 (2H, d, J=4.4 Hz),3.65-3.35 (3H, m), 2.50-1.10 (15 H, m), 1.42 (3H, t, J=6.6 Hz).

MS (ESI) m/z: 411 (M+H)⁺.

Step 2.(R)-3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using (R)-ethyl3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 66 Step 1) instead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

MS (ESI) m/z: 383 (M+H)⁺, 381 (M−H)⁻.

Step 3.(R)-3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 1 using(R)-3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 66 Step 2) and isoxazol-3-amine instead ofcis-4-(trifluoromethyl)cyclohexanecarboxylic acid and(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride withpreparative HPLC purification.

MS (ESI) m/z: 449 (M+H)⁺, 447 (M−H)⁻.

HPLC Retention time: 2.65 min (Method B).

Example 67(R)—N-(2-amino-2-oxoethyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1. (R)-ethyl3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using (R)-ethyl3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifuluoroacetic acid) salt(EXAMPLE 34 Step 1) and 3-trifluoromethylbenzoic acid instead ofammonium chloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.

¹H-NMR (CDCl₃) δ 8.28 (1H, dd, J=4.4, 1.5 Hz), 7.80 (1H, s), 7.73-7.63(2H, m), 7.58-7.45 (2H, m), 7.38 (1H, dd, J=8.8, 4.4 Hz), 4.65-4.55 (2H,m), 4.46 (2H, q, J=7.3 Hz), 4.29 (1H, m), 3.65 (1H, m), 3.44 (1H, m),2.33-2.01 (3H, m), 1.84 (1H, m), 1.45 (3H, t, J=7.3 Hz).

MS (ESI) m/z: 423 (M+H)⁺.

Step 2.(R)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using (R)-ethyl3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 67 Step 1) instead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

¹H-NMR (CDCl₃) δ 8.19 (1H, d, J=4.4 Hz), 7.80 (1H, s), 7.76-7.64 (2H,m), 7.63-7.48 (3H, m), 4.76 (1H, dd, J=9.5, 4.4 Hz), 4.66 (1H, m), 4.28(1H, d, J=9.5 Hz), 3.92 (1H, m), 3.46 (1H, m), 2.45-2.11 (3H, m), 1.82(1H, m). A signal due to COON was not observed.

MS (ESI) m/z: 395 (M+H)⁺, 393 (M−H)⁻.

Step 3.(R)—N-(2-amino-2-oxoethyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using 2-aminoacetamide and(R)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 67 Step 2) instead of ammonium chloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid with preparative HPLC purification.

MS (ESI) m/z: 451 (M+H)⁺, 449 (M−H)⁻.

HPLC Retention time: 1.32 min (Method C).

Example 68 to 74

The following examples, EXAMPLE 68-74, were prepared according to theprocedure similar to that described in the Step 5 of the EXAMPLE 31,using(R)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 67 Step 2) and the appropriate precursor of amine, R²—NH₂.The following examples, EXAMPLE 68 to 74, were purified by preparativeHPLC.

TABLE 8 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R²Chemical Name Method (min.) (M + H)+ 68

(R)-N-(2-morpholinoethyl)-3- ((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.42 507 69

(R)-N-(2-hydroxyethyl)-3- ((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.35 438 70

(R)-N-(2-methoxyethyl)-3- ((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.50 452 71

(R)-N-((1-hydroxycyclohexyl) methyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.64 506 72

(R)-N-phenyl-3-((1-(3-(trifluoro- methyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.80 470 73

(R)-N-(pyridin-2-ylmethyl)-3- ((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy) picolinamide Method C 1.52 485 74

(R)-N-benzyl-3-((1-(3-(trifluoro- methyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide Method C 1.74 484

Example 75N-(pyridin-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1.3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride (EXAMPLE 1 Step 3) andtrans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of ammoniumchloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.

¹H-NMR (CDCl₃) δ 8.20 (1H, d, J=4.4 Hz), 7.60 (1H, d, J=7.3 Hz), 7.59(1H, s), 7.41 (1H, dd, J=8.1, 4.4 Hz), 5.58 (1H, brs), 4.44 (1H, m),4.24 (2H, d, J=5.1 Hz), 3.70 (1H, m), 3.52 (1H, m), 2.50-1.80 (11H, m),1.70-1.20 (3H, m).

MS (ESI) m/z: 400 (M+H)⁺.

Step-2.N-(pyridin-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

To a stirred mixture of3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide(30 mg, 0.08 mmol, EXAMPLE 75 Step 1),4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (3.47 mg,6.00 micromol), cesium carbonate (0.10 g, 0.30 mmol), andtris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃) (1.56 mg, 1.50micromol) in 1,4-dioxane (2 mL) was added 2-bromopyridine (14 mg, 0.09mmol) at room temperature. After being stirred at 120° C. for 12 h undermicrowave irradiation, water was added to the mixture. The mixture wasextracted with ethyl acetate twice. The extracts were combined and driedover magnesium sulfate and concentrated in vacuo to afford an oil. Theresidual oil was purified by preparative HPLC.

MS (ESI) m/z: 477 (M+H)⁺, 475 (M−H)⁻.

HPLC Retention time: 1.75 min (Method C).

Example 76N-(pyrazin-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 2 of EXAMPLE 75 using 2-chloropyrazine instead of 2-bromopyridinewith preparative HPLC purification.

MS (ESI) m/z: 478 (M+H)⁺.

HPLC Retention time: 1.66 min (Method C).

Example 77N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1. 4-(iodomethyl)tetrahydro-2H-pyran-4-ol

A mixture of trimethylsulfoxonium chloride (3.08 g, 23.73 mmol) and 2 Naq. sodium hydroxide (11.33 mL, 22.65 mmol) in tetrahydrofuran (13 mL)was heated at 50° C. for 1 h. 2.16 g (21.57 mmol) oftetrahydro-4H-pyran-4-one was added to the mixture and the mixture wasstirred at 50° C. for 30 min. After cooling to room temperature, 3.56 g(23.73 mmol) of sodium iodide and 2 N hydrochloric acid (10.8 mL, 21.57mmol) were added to the mixture. After being stirred at room temperaturefor 19 h, ethyl acetate was added to the mixture. The mixture wasextracted with ethyl acetate three times and the extracts were combined.The extracts were dried over sodium sulfate and concentrated in vacuo toafford a beige solid. The residual solid was recrystallized fromacetonitrile to afford 3.13 g (55%) of the title compound.

¹H NMR 3.85-3.65 (m, 4H), 3.36 (s, 2H), 1.85-1.55 (m, 4H)

A signal due to OH was not observed.

MS (ESI) m/z: 243 (M+H)⁺.

Step 2.N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

To a solution of3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide(105 mg, 0.263 mmol, EXAMPLE 75 Step 1) in 1-Methyl-2-pyrrolidone (5 mL)was added sodium hydride (60% oil dispersant, 16 mg, 0.394 mmol) atambient temperature. After being stirred at room temperature for 1 h,4-(iodomethyl)tetrahydro-2H-pyran-4-ol (76 mg, 0.315 mmol, EXAMPLE 77Step 1) was added to the mixture. The mixture was heated at 70° C. andstirred for 3 days. After cooling to room temperature, aq. citric acidwas added to the mixture. The mixture was extracted with ethyl acetatetwice and washed successively with aq. sodium thiosulfate, aq. sodiumbicarbonate, and brine. The extracts were combined and dried over sodiumsulfate and concentrated in vacuo to afford 72 mg of crude oil. Theresidual oil was purified by preparative HPLC purification.

MS (ESI) m/z: 514 (M+H)⁺.

HPLC Retention time: 1.44 min (Method C).

Example 78(R)—N-(pyridin-2-yl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1.(R)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 5 of EXAMPLE 31 using (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride (EXAMPLE 1 Step 3) and 3-(trifluoromethyl)benzoic acidinstead of ammonium chloride and5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.

¹H-NMR (CDCl₃) δ 8.20 (1H, d, J=4.4 Hz), 7.79 (1H, s), 7.75-7.60 (3H,m), 7.60-7.47 (2H, m), 7.40 (1H, dd, J=8.0, 4.4 Hz), 5.56 (1H, brs),4.62 (2H, d, J=6.6 Hz), 4.29 (1H, d, J=7.3 Hz), 3.81 (1H, dt, J=9.5, 6.6Hz), 3.43 (1H, m), 2.50-2.10 (3H, m), 1.82 (1H, m).

MS (ESI) m/z: 394 (M+H)⁺, 392 (M−H)⁻.

Step 2.(R)—N-(pyridin-2-yl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 2 of EXAMPLE 75 using(R)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide(EXAMPLE 78 Step 1) instead of3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamidewith preparative HPLC purification.

MS (ESI) m/z: 471 (M+H)⁺, 469 (M−H)⁻.

HPLC Retention time: 1.74 min (Method C).

Example 793-(((2R,4R)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(pyridin-2-yl)picolinamide

Step 1. (2R,4R)-1-tert-butyl 2-methyl4-(benzyloxymethoxy)pyrrolidine-1,2-dicarboxylate

To a mixture of (2R,4R)-1-tert-butyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate (2.12 g, 8.65 mmol) andN,N-diisopropylethylamine (3.01 mL, 17.3 mmol) in dichloromethane (30mL) was added benzyl chloromethyl ether (2.71 g, 17.3 mmol). Afterstirring at room temperature for 18 h, the mixture was poured intowater. The aqueous layer was extracted with dichloromethane three times.The combined organic layers were dried over magnesium sulfate andconcentrated in vacuo to afford an oil. The residual oil was purified bysilica gel column chromatography (ethyl acetate/hexane 1:4 to 1:3) togive 2.29 g (72%) of the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ 7.40-7.26 (5H, m), 4.77-4.70 (2H, m), 4.63-4.50 (2H,m), 4.35-4.25 (2H, m), 3.73 (3H, s), 3.75-3.50 (2H, m), 2.45-2.29 (2H,m), 1.50-1.40 (9H, m).

MS (ESI) m/z: 366 (M+H)⁺.

Step 2. (2R,4R)-tert-butyl4-(benzyloxymethoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a mixture of (2R,4R)-1-tert-butyl 2-methyl4-(benzyloxymethoxy)pyrrolidine-1,2-dicarboxylate (2.29 g, 6.27 mmol,EXAMPLE 79 Step 1) and lithium chloride (586 mg, 13.8 mmol) in ethanol(25 mL) was added sodium borohydride (522 mg, 13.8 mmol) at 0° C., andthe mixture was stirred at room temperature for 24 h. Then, the mixturewas poured into water, and the aqueous layer was extracted with ethylacetate three times. The combined organic layers were dried overmagnesium sulfate and concentrated in vacuo. The residual oil waspurified by silica gel column chromatography (ethyl acetate/hexane 1:2to 2:3) to give 1.72 g (81%) of the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ 7.40-7.25 (5H, m), 4.79 (2H, s), 4.65-3.35 (8H, m),2.30-2.18 (1H, m), 1.80-1.65 (1H, m), 1.47 (9H, m). A signal due to OHwas not observed.

MS (ESI) m/z: 338 (M+H)⁺.

Step 3. ethyl3-(((2R,4R)-4-(benzyloxymethoxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using (2R,4R)-tert-butyl4-(benzyloxymethoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (EXAMPLE79 Step 2) and ethyl 3-hydroxypicolinate instead of(R)-pyrrolidin-2-ylmethanol and 5-chloropyridin-3-ol.

¹H-NMR (CDCl₃) δ 8.42-8.20 (1H, m), 7.6-7.25 (7H, m), 4.82-3.40 (10H,m), 4.43 (2H, q, J=7.3 Hz), 2.48-2.10 (2H, m), 1.47 (9H, s), 1.41 (3H,t, J=7.3 Hz).

MS (ESI) m/z: 487 (M+H)⁺.

Step 4. ethyl3-(((2R,4R)-4-(benzyloxymethoxy)pyrrolidin-2-yl)methoxy)picolinate

To an ice-cold solution of ethyl3-(((2R,4R)-4-(benzyloxymethoxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate(845 mg, 1.74 mmol, EXAMPLE 79 Step 3) in dichloromethane (12 mL) wasadded trifluoroacetic acid, and the mixture was stirred at 0° C. for 1h. The mixture was warmed to room temperature and stirred for 1 h atthis temperature, then the mixture was concentrated in vacuo to affordan oil. The residual oil was purified by NH-gel column chromatography(ethyl acetate only to methanol/ethyl acetate 1:10) to give 200 mg (30%)of the title compound as a pale yellow oil.

¹H-NMR (CDCl₃) δ 8.30 (1H, d, J=4.4 Hz), 7.41-7.23 (7H, m), 4.78 (2H,s), 4.60 (2H, s), 4.44 (2H, q, J=7.3 Hz), 4.50-4.32 (1H, m), 4.13-4.02(2H, m), 3.63-3.51 (1H, m), 3.18-3.05 (2H, m), 2.31-2.20 (1H, m),1.80-1.70 (1H, m), 1.42 (3H, t, J=7.3 Hz). A signal due to NH was notobserved.

MS (ESI) m/z: 387 (M+H)⁺.

Step 5. ethyl3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 3 using ethyl3-(((2R,4R)-4-(benzyloxymethoxy)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 79 Step 4) and trans-4-(trifluoromethyl)cyclohexanecarboxylicacid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride and indole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ 8.28-8.22 (1H, m), 7.63-7.58 (1H, m), 7.43-7.22 (6H,m), 4.90-4.78 (2H, m), 4.80-4.10 (6H, m), 4.42 (2H, q, J=7.4 Hz),3.68-3.51 (2H, m), 2.50-1.21 (12H, m), 1.41 (3H, t, J=7.4 Hz).

MS (ESI) m/z: 565 (M+H)⁺.

Step 6.3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using ethyl3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 79 Step 5) instead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

¹H-NMR (CDCl₃) δ 8.30-8.18 (1H, br), 7.85-7.75 (1H, br), 7.61-7.50 (1H,br), 7.40-7.20 (5H, m), 4.88-3.50 (10H, m), 2.40-1.65 (8H, m), 1.60-1.18(4H, m). A signal due to COOH was not observed.

MS (ESI) m/z: 537 (M+H)⁺, 535 (M−H)⁻.

Step 7.3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(pyridin-2-yl)picolinamide

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 1 using3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 79 Step 6) and pyridin-2-amine instead ofcis-4-(trifluoromethyl)cyclohexanecarboxylic acid and(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride.

MS (ESI) m/z: 613 (M+H)⁺, 611 (M−H)⁻.

Step 8.3-(((2R,4R)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(pyridin-2-yl)picolinamide

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 79 using3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(pyridin-2-yl)picolinamide(EXAMPLE 79 Step 7) instead of ethyl3-(((2R,4R)-4-(benzyloxymethoxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinatewith preparative HPLC purification.

MS (ESI) m/z: 493 (M+H)⁺, 491 (M−H)⁻.

HPLC Retention time: 2.54 min (Method B).

Example 803-(((2R,4R)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide

Step 1.3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 1 using3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 79 Step 6) and isoxazol-3-amine instead ofcis-4-(trifluoromethyl)cyclohexanecarboxylic acid and(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride.

MS (ESI) m/z: 603 (M+H)⁺, 601 (M−H)⁻.

Step 23-(((2R,4R)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 79 using3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(pyridin-2-yl)picolinamide(EXAMPLE 80 Step 1) instead of ethyl3-(((2R,4R)-4-(benzyloxymethoxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinatewith preparative HPLC purification.

MS (ESI) m/z: 483 (M+H)⁺, 481 (M−H)⁻.

HPLC Retention time: 2.52 min (Method B).

Example 813-(((2R,4R)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(oxazol-2-yl)picolinamide

Step 1.3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(oxazol-2-yl)picolinamide

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 3 using3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 79 Step 6) and oxazol-2-amine instead ofindole-2-carboxylic acid and (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride.

MS (ESI) m/z: 603 (M+H)⁺, 601 (M−H)⁻.

Step 2.3-(((2R,4R)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(oxazol-2-yl)picolinamide

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 79 using3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(oxazol-2-yl)picolinamide(EXAMPLE 81 Step 1) instead of ethyl3-(((2R,4R)-4-(benzyloxymethoxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinatewith preparative HPLC purification.

MS (ESI) m/z: 483 (M+H)⁺, 481 (M−H)⁻.

HPLC Retention time: 1.39 min (Method C).

Example 82N-benzyl-3-(((2R,4S)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

Step 1. ethyl3-(((2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using (2R,4S)-tert-butyl4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(PCT Int. Appl., WO2009026197) and ethyl 3-hydroxypicolinate instead of(R)-pyrrolidin-2-ylmethanol and 5-chloropyridin-3-ol.

¹H-NMR (CDCl₃) δ 8.25 (1H, brd, J=4.0 Hz), 7.5-7.3 (2H, m), 4.52 (1H,m), 4.42 (2H, q, J=7.3 Hz), 4.3-4.1 (3H, m), 3.6-3.3 (2H, m), 2.27 (1H,m), 2.05 (1H, m), 1.44 (9H, s), 1.42 (3H, t, J=7.3 Hz), 0.87 (9H, s),0.08 (6H, s).

MS (ESI) m/z: 481 (M+H)⁺.

Step 2. ethyl 3-(((2R,4S)-4-hydroxypyrrolidin-2-yl)methoxy)picolinatedihydrochloride

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using ethyl3-(((2R,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 82 Step 1) instead of (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

MS (ESI) m/z: 267 (M+H)⁺.

Step 3. ethyl3-(((2R,4S)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 3 using ethyl3-(((2R,4S)-4-hydroxypyrrolidin-2-yl)methoxy)picolinate dihydrochloride(EXAMPLE 82 Step 2) and trans-(4-trifluoromethyl)cyclohexanecarboxylicacid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride and indol-2-carboxylic acid.

¹H-NMR (CDCl₃) d 8.27 (1H, dd, J=3.7, 2.2 Hz), 7.39 (2H, m), 4.74 (1H,br), 4.57 (2H, m), 4.42 (2H, q, J=7.3 Hz) 4.09 (1H, m), 3.80 (1H, dd,J=10.5, 5.1 Hz), 3.54 (1H, brd, J=10.5 Hz), 2.5-2.4 (1H, m), 2.32 (1H,m), 2.2-1.9 (5H, m), 1.43 (3H, t, J=7.3 Hz), 1.7-1.2 (6 H, m).

MS (ESI) m/z: 445 (M+H)⁺.

Step 4.3-(((2R,4S)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using ethyl3-(((2R,4S)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate(EXAMPLE 82 Step 3) instead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

MS (ESI) m/z: 415 (M−H)⁺.

Step 5.N-benzyl-3-(((2R,4S)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using3-(((2R,4S)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 82 Step 4) and benzylamine instead of indol-2-carboxylicacid and (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate withpreparative HPLC purification.

MS (ESI) m/z: 506 (M+H)⁺.

HPLC Retention time: 1.53 min (Method C).

Example 833-(((2R,4S)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(pyridin-2-yl)picolinamide

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using3-(((2R,4S)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinicacid (EXAMPLE 82 Step 4) and 2-aminopyridine instead ofindol-2-carboxylic acid and (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate withpreparative HPLC purification.

MS (ESI) m/z: 493 (M+H)⁺, 491 (M−H)⁻.

HPLC Retention time: 1.49 min (Method C).

The starting materials of following EXAMPLE 84-95, tert-butyl3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate, tert-butyl1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate, andtert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate were prepared fromthe corresponding N-Boc amino acid methyl or ethyl ester by similarmethod as described in step 2 of Example 79. The corresponding N-Bocamino acid methyl or ethyl ester was prepared by usual manner from thecorresponding amino acid.

Example 845-chloro-3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide

Step 1. tert-butyl3-(((5-chloropyridin-3-yl)oxy)methyl)-3-methylpyrrolidine-1-carboxylate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using tert-butyl3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate instead of(R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ 8.20 (2H, s), 7.27 (1H, s), 3.81 (2H, s), 4.45 (1H, m),3.44 (3H, m), 3.17 (1H, dd, J=15.4, 1.0 Hz), 1.99 (1H, m), 1.73 (1H, m),1.46 (9H, s), 1.23 (3H, s)

MS (ESI) m/z: 327 (M+H)⁺.

Step 2.3-((1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl)methoxy)-5-chloropyridine1-oxide

The title compound was prepared according to the procedure described inStep 2 of EXAMPLE 29 using tert-butyl3-(((5-chloropyridin-3-yl)oxy)methyl)-3-methylpyrrolidine-1-carboxylate(EXAMPLE 84, Step 1) instead of (R)-tert-butyl2-((5-chloropyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ 7.92 (1H, s), 7.87 (1H, s), 6.91 (1H, s), 3.79 (2H, s),3.5-3.2 (3H, m), 3.2-3.1 (1H, m), 1.92 (1H, m), 1.70 (1H, m), 1.47 (9H,s), 1.21 (3H, s)

MS (ESI) m/z: 343 (M+H)⁺.

Step 3. tert-butyl3-(((5-chloro-2-cyanopyridin-3-yl)oxy)methyl)-3-methylpyrrolidine-1-carboxylate

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 29 using3-((1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl)methoxy)-5-chloropyridine1-oxide (EXAMPLE 84, Step 2) instead of(R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-5-chloropyridine1-oxide.

¹H-NMR (CDCl₃) δ 8.26 (1H, d, J=1.3 Hz), 7.35 (1H, d, J=2.0 Hz), 3.91(2H, s), 3.48 (3H, m), 3.21 (1H, m), 2.04 (1H, m), 1.81 (1H, m), 1.46(9H, s), 1.30 (3H, s)

MS (ESI) m/z: 252 (M+H−Boc)⁺.

Step 4. 5-chloro-3-(((3-methylpyrrolidin-3-yl)methoxy)picolinonitriledihydrochloride

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using tert-butyl3-(((5-chloro-2-cyanopyridin-3-yl)oxy)methyl)-3-methylpyrrolidine-1-carboxylate(EXAMPLE 84, Step 4) instead of (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

MS (ESI) m/z: 252 (M+H)⁺.

Step 5.5-chloro-3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinonitrile

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using5-chloro-3-((3-methylpyrrolidin-3-yl)methoxy)picolinonitriledihydrochloride (EXAMPLE 84, Step 4) andtrans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride andindole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ 8.28 (1H, dd, J=5.9, 1.5 Hz), 7.35 (1H, dd, J=5.9, 1.5Hz), 3.93 (2H, s), 3.8-3.5 (3H, m), 3.37 (1H, m), 2.2-1.9 (2H, m),2.18-1.75 (6H, m), 1.58 (2H, m), 1.50-1.22 (2H, m), 1.33 (3H, s)

MS (ESI) m/z: 430 (M+H)⁺.

Step 6.5-chloro-3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 2 of EXAMPLE 1 using5-chloro-3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinonitrile(EXAMPLE 29 Step 3) instead of (R)-tert-butyl2-((2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate withpreparative HPLC purification.

¹H-NMR (CDCl₃) δ 8.16 (1H, d, J=2.2 Hz), 7.46 (1H, br), 7.36 (1H, d,J=1.5 Hz), 5.55 (1 H, br), 3.89 (2H, m), 3.8-3.5 (3H, m), 3.33 (1H, dd,J=11.0, 10.2 Hz), 2.4-1.2 (12H, m), 1.33 (3H, s)

MS (ESI) m/z: 448 (M+H)⁺.

HPLC Retention time: 1.57 min (Method C).

Example 855-chloro-3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inEXAMPLE 84 using tert-butyl1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead oftert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate withpreparative HPLC purification.

¹H-NMR (CDCl₃) δ 8.21 (1H, d, J=2.0 Hz), 7.47 (1H, br), 7.36 (1H, d,J=2.0 Hz), 5.56 (1H, br), 4.30-4.05 (2H, m), 3.94 (1H, dd, J=12.5, 11.9Hz), 3.86 (1H, m), 3.8-3.6 (1H, m), 3.6-3.4 (1H, m), 2.4-2.2 (1H, m),2.1-1.8 (5H, m), 1.7-1.5 (3H, m), 1.5-1.2 (2H, m), 1.2-1.1 (1H, m), 0.62(1H, m)

MS (ESI) m/z: 446 (M+H)⁺.

HPLC Retention time: 1.54 min (Method C).

Example 86N-benzyl-3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide

Step 1. ethyl3-((1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using tert-butyl3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate and ethyl3-hydroxypicolinate instead of (R)-tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate and 5-chloropyridin-3-ol.

¹H-NMR (CDCl₃) δ 8.29 (1H, d, J=3.7 Hz), 7.4-7.2 (2H, m), 4.45 (2H, q,J=7.3 Hz), 3.85 (2H, qAB, J=9.5 Hz), 3.5-3.4 (3H, m), 3.17 (1H, dd,J=16.1, 1.0 Hz), 2.2-1.95 (1H, m), 1.74 (1H, m), 1.46 (9H, s), 1.42 (3H,t, J=7.3 Hz), 1.26 (3H, s)

MS (ESI) m/z: 365 (M+H)⁺.

Step 2. ethyl 3-((3-methylpyrrolidin-3-yl)methoxy)picolinatedihydrochloride

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using ethyl3-((1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl)methoxy)picolinate(EXAMPLE 86, Step 1) instead of (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

MS (ESI) m/z: 265 (M+H)⁺.

Step 3. ethyl3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using ethyl3-((3-methylpyrrolidin-3-yl)methoxy)picolinate dihydrochloride (EXAMPLE86, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acidinstead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochlorideand indole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ 8.31 (1H, br), 7.42-7.25 (2H, m), 4.45 (2H, m), 3.86(2H, qAB, J=8.6 Hz), 3.5-3.8 (3H, m), 3.32 (1H, dd, J=15.2, 10.5 Hz),2.34 (1H, m), 2.2-1.5 (10H, m), 1.2-1.5 (7H, m)

MS (ESI) m/z: 443 (M+H)⁺.

Step 4.3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using ethyl3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinate(EXAMPLE 86 Step 3) in stead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

MS (ESI) m/z: 415 (M+H)⁺, 413 (M−H)⁻.

Step 5.N-benzyl-3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using benzylamine and3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinicacid (EXAMPLE 86, Step 4) instead of(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride andindole-2-carboxylic acid with preparative HPLC purification.

MS (ESI) m/z: 504 (M+H)⁺.

HPLC Retention time: 1.72 min (Method C).

Example 873-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)picolinamide

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using (tetrahydro-2H-pyran-4-yl)methanamine and3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinicacid (EXAMPLE 86, Step 4) instead of(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride andindole-2-carboxylic acid with preparative HPLC purification.

MS (ESI) m/z: 512 (M+H)⁺.

HPLC Retention time: 1.53 min (Method C).

Example 88N-benzyl-3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide

Step 1. tert-butyl1-(((2-(ethoxycarbonyl)pyridin-3-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using tert-butyl

-   1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and ethyl-   3-hydroxypicolinate instead of (R)-tert-butyl-   2-(hydroxymethyl)pyrrolidine-1-carboxylate and 5-chloropyridin-3-ol.

¹H-NMR (CDCl₃) δ 8.30 (1H, d, J=4.4 Hz), 7.5-7.2 (2H, m), 4.45 (2H, q,J=6.6 Hz), 1.57 (1H, m), 1.45 (9H, s), 1.42 (3H, t, J=6.6 Hz), 0.95 (1H,m), 0.63 (1H, m)

MS (ESI) m/z: 363 (M+H)⁺.

Step 2. ethyl 3-((3-azabicyclo[3.1.0]hexan-1-ylmethoxy)picolinatedihydrochloride

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using ethyl tert-butyl1-(((2-(ethoxycarbonyl)pyridin-3-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (EXAMPLE 88, Step 1) instead of (R)-tert-butyl2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate.

MS (ESI) m/z: 263 (M+H)⁺, 261 (M−H)⁻.

Step 3. ethyl3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using ethyl3-((3-azabicyclo[3.1.0]hexan-1-ylmethoxy)picolinate dihydrochloride(EXAMPLE 88, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylicacid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride and indole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ 8.32 (1H, m), 7.40-7.25 (2H, m), 4.41 (2H, dq, J=7.3,3.7 Hz), 4.3-3.6 (5H, m), 3.48 (1H, m), 2.29 (1H, m), 2.05 (3H, m), 1.87(2H, m), 1.8-1.2 (8H, m), 1.02 (1 H, m), 0.59 (1H, m)

MS (ESI) m/z: 441 (M+H)⁺.

Step 4.3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinic acid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using ethyl3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinate (EXAMPLE 88 Step 3) in stead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

MS (ESI) m/z: 413 (M+H)⁺, 411 (M−H)⁻.

Step 5.N-benzyl-3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using benzylamine and3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinic acid (EXAMPLE 88, Step 4) instead of(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride andindole-2-carboxylic acid with preparative HPLC purification.

MS (ESI) m/z: 502 (M+H)⁺.

HPLC Retention time: 1.67 min (Method C).

Example 89 to 91

The following examples, EXAMPLE 89-91, were prepared according to theprocedure similar to that described in the Step 1 of the EXAMPLE 3,using the3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinic acid (EXAMPLE 88 Step 4) and appropriate precursor ofamine, R²—NH₂ with preparative HPLC purification.

TABLE 9 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R²Chemical Name Method (min.) (M + H)+ 89

N-((tetrahydro-2H-pyran-4-yl) methyl)-3-((3-(trans-4-(trifluoro-methyl)cyclohexanecarbonyl)-3- azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide Method C 1.50 510 90

N-(pyridin-2-yl)-3-((3-trans-4- (trifluoromethyl)cyclohexane-carbonyl)-3-azabicyclo[3.1.0] hexan-1-yl)methoxy) picolinamide Method C1.67 489 91

N-(tetrahydro-2H-pyran-4-yl)- 3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3- azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide Method C 1.46 496

Example 92N-(pyridin-2-yl)-3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide

Step 1. ethyl3-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 1 of EXAMPLE 29 using tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate and ethyl 3-hydroxypicolinateinstead of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate and5-chloropyridin-3-ol.

¹H-NMR (CDCl₃) δ 8.29 (1H, brd, J=4.4 Hz), 7.39 (1H, dd, J=8.1, 4.4 Hz),7.32 (1H, dd, J=8.1, 1.5 Hz), 4.45 (2H, q, J=7.3 Hz), 4.00 (2H, m),3.7-3.3 (3H, m), 3.23 (1H, dd, J=11.0, 7.3 Hz), 2.74 (1H, m), 2.10 (1H,m), 1.70 (1H, m), 1.47 (9H, s), 1.42 (3H, t, J=7.3 Hz)

MS (ESI) m/z: 351 (M+H)⁺.

Step 2. ethyl 3-(pyrrolidin-3-ylmethoxy)picolinate

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 79 using ethyl3-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methoxy)picolinate (EXAMPLE92, Step 1) instead of ethyl3-(((2R,4R)-4-(benzyloxymethoxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

MS (ESI) m/z: 251 (M+H)⁺.

Step 3. ethyl3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinate

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using ethyl 3-(pyrrolidin-3-ylmethoxy)picolinate(EXAMPLE 92, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylicacid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamidedihydrochloride and indole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ 8.32 (1H, t, J=4.4 Hz), 7.39 (1H, m), 7.32 (1H, dd,J=7.4, 3.7 Hz), 4.45 (2H, dq, J=7.4, 2.9 Hz), 4.11 (1H, m), 3.96 (1H,dd, J=16.2, 7.3 Hz), 3.8-3.3 (4H, m), 2.85 (1H, m), 2.38 (1H, m),2.2-1.2 (11H, m), 1.43 (3H, dt, J=7.3, 2.2 Hz)

MS (ESI) m/z: 429 (M+H)⁺.

Step 4.3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinicacid

The title compound was prepared according to the procedure described inStep 4 of EXAMPLE 31 using ethyl3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinate(EXAMPLE 92 Step 3) in stead of ethyl5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.

MS (ESI) m/z: 401 (M+H)⁺, 399 (M−H)⁻.

Step 5.N-(pyridin-2-yl)-3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide

The title compound was prepared according to the procedure described inStep 3 of EXAMPLE 1 using benzylamine and3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinicacid (EXAMPLE 92, Step 4) instead of(R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride andindole-2-carboxylic acid with preparative HPLC purification.

MS (ESI) m/z: 490 (M+H)⁺.

HPLC Retention time: 1.64 min (Method C).

Example 93 to 95

The following examples, EXAMPLE 93-95, were prepared according to theprocedure similar to that described in the Step 1 of the EXAMPLE 3,using the3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinicacid (EXAMPLE 92, Step 4) and appropriate precursor of amine, R²—NH₂with preparative HPLC purification.

TABLE 10 HPLC MS HPLC Retention (ESI): Gradient Time m/z EXAMPLES R²Chemical Name Method (min.) (M + H)+ 93

N-((tetrahydro-2H-pyran-4-yl) methyl)-3-((1-(trans-4-(trifluoromethyl)cyclohexane- carbonyl)pyrrolidin-3-yl)methoxy)picolinamide Method C 1.46 498 94

N-(pyridin-2-yl)-3-((1-(trans-4- (trifluoromethyl)cyclohexane-carbonyl)pyrrolidin-3-yl) methoxy)picolinamide Method C 1.64 477 95

N-(tetrahydro-2H-pyran-4-yl)- 3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin- 3-yl)methoxy)picolinamide Method C 1.43484

Pharmacological Assays

The ability of the picolinamide derivatives of the formula (I) toinhibit the Na_(V1.3), Na_(V1.7) and Na_(V1.5) channels was measured byFRET assay and electrophysiology assay described below.

FRET Assay

This screen is used to determine the effects of compounds on humanNa_(V1.3), human Na_(V1.7), and human Na_(V1.5) channels, utilising thecell imaging technology by Hamamatsu Photonics's Functional DrugScreening System (FDSS). This experiment is based on FRET (FluorescenceResonance Energy Transfer) and uses two fluorescent molecules. The firstmolecule, Oxonol (DiSBAC2(3)), is a highly fluorescent, negativelycharged, hydrophobic ion that “senses” the trans-membrane electricalpotential. In response to changes in membrane potential, it can rapidlyredistribute between two binding sites on opposite sides of the plasmamembrane. The voltage dependent redistribution is transduced into aratiometric fluorescent readout via a second fluorescent molecule(Coumarin (CC2-DMPE)) that binds specifically to one face of the plasmamembrane and functions as a FRET partner to the mobile voltage-sensingion. To enable the assay to work, the channels have to bepharmacologically held in the open state. This is achieved by treatingthe cells with veratridine.

Cell Maintenance:

Each HEK293 cells expressing human Na_(V1.3) channels and HEK293 cellsexpressing human Na_(V1.5) channels were grown in T225 flasks, in a 5%CO₂ humidified incubator to about 80% confluence. Media compositionconsisted of Dulbecco's Modified Eagle Medium (high glucose), 10% fetalcalf serum (FCS), 100 units/ml Penicillin, 100 microgram/ml Streptomycinand 500 microgram/ml Geneticine.

CHO cells expressing human Na_(V1.7) channels were grown in T225 flasks,in a 5% CO₂ humidified incubator to about 80% confluence. Mediacomposition consisted of HAM/F12 with Glutamax I, 10% fetal calf serum(FCS), 100 units/ml Penicillin and 100 microgram/ml Hygromycin.

Protocol:

-   -   Seed each cell lines (1.5×10⁴ cells/well) into poly-D-lysine        coated 384-well plates prior to experimentation.    -   Incubate at 37° C. in 5% CO₂ for 24 hours.    -   Wash each well with buffer #1 (140 mM NaCl, 4.5 mM KCl, 10 mM        D-Glucose, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, pH 7.4 adjusted        with NaOH) twice using plate washer.    -   Add 1st loading solution containing 5 μM CC2-DMPE and 0.02%        Pluronic F-127 in buffer #1.    -   Incubate the plate at room temperature in dark for 0.5 hours.    -   Wash each well with buffer #2 (160 mM Choline, 10 mM D-Glucose,        0.1 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, pH 7.4 adjusted with KOH)        twice using plate washer.    -   Add 2nd loading solution containing 15 μM DiSBAC2(3), 0.5 mM        VABSC-1, 10 μM veratridine and 0.004% Pluronic F-127 in buffer        #2.    -   Add compound solutions into the assay plate and leave the plate        for 30 minutes under the dark at room temperature.    -   Measure by FDSS.

The data was analyzed and reported as normalized ratios of intensitiesmeasured in the 465 nm and 575 nm channels. The process of calculatingthese ratios was performed as follows:

“FI465B”=the mean of fluorescence intensity as baseline (before Na+ligand addition) at 465 nm

“FI575B”=the mean of fluorescence intensity as baseline (before Na+ligand addition) at 575 nm

“FI465Max”=maximum fluorescence intensity at 465 nm after Na+stimulation

“FI575 Min”=minimum fluorescence intensity at 575 nm after Na+stimulation

“FR”=fluorescence ratio=(FI465Max/FI575 Min)−(FI465B/FI575B)

$\begin{matrix}{{{Inhibition}\mspace{14mu} (\%)} = {100 - {\frac{\begin{matrix}{\left( {{FR}\mspace{14mu} {of}\mspace{14mu} {each}\mspace{14mu} {well}} \right) -} \\\left( {{median}\mspace{14mu} {FR}\mspace{14mu} {in}\mspace{14mu} {positive}\mspace{14mu} {controls}} \right)\end{matrix}}{\begin{matrix}{\left( {{median}\mspace{14mu} {FR}\mspace{14mu} {in}\mspace{14mu} {negative}\mspace{14mu} {controls}} \right) -} \\\left( {{median}\mspace{14mu} {FR}\mspace{14mu} {in}\mspace{14mu} {negative}\mspace{14mu} {controls}} \right)\end{matrix}} \times 100}}} & \left\lbrack {{Math}.\mspace{14mu} 1} \right\rbrack\end{matrix}$

This analysis was performed using a computerized specific programdesigned for FDSS generated data. Fluorescence ratio values were plottedusing XLfit to determine an IC₅₀ value for each compound.

Electrophysiology Assay

Whole cell patch clamp recording was used to assess the efficacy orselectivity of Na channel blocker on human Na_(V1.3) (hSCN3A) expressingHEK293 cells or human Na_(V1.7) (hSCN9A) expressing CHO cells. HumanNa_(V1.3) expressing HEK293 cells were grown in growth media whichcomprised: DMEM, 10% heat-inactivated FBS (Hyclone Laboratories Inc),100 microgram/ml Penicillin/100 U/ml Streptomycin, 150 microgram/mlZeocin, 3 microgram/ml Geneticin. Human Na_(V1.7) expressing CHO cellswere grown in growth media which comprised: HAM/F-12, 9%heat-inactivated FBS (Hyclone Laboratories Inc), 100 microgram/mlPenicillin/100 U/ml Streptomycin, 100 microgram/ml Hygromycin.

Na channel expressing cells were dissociated by 0.05% Trypsine-EDTA, andthen seeded on cover glass for 24-48 hr.Glass pipettes were pulled to a tip diameter of 1-2 micrometer on apipette puller. The pipettes were filled with the intracellular solutionand a chloridized silver wire was inserted along its length, which wasthen connected to the headstage of the voltage-clamp amplifier (AxonInstruments or HEKA electronik). The extracellular recording solutionconsists of (mM): 140 NaCl, 5 KCl, 2 CaCl₂, 1 MgCl₂, 10 HEPES, 10Glucose, pH 7.4 adjusted with NaOH. The internal solution consists of(mM): 120 CsF, 15 NaCl, 10 EGTA, 10 HEPES, pH 7.2 adjusted with CsOH;Upon insertion of the pipette tip into the bath, the pipette resistancewas noted (acceptable range is between 1-3 megaohm). The junctionpotential between the pipette and bath solutions was zeroed on theamplifier. After establishing the whole-cell configuration,approximately 10 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated (>80%) and was monitored continuously.The normalized steady-state inactivation curve was constructed using 500msec (for vehicle) or 60 sec (for drugs) conditioning pulse to differentpotentials followed immediately by the test pulse to 0 mV. Peak currentswere plotted as fraction of the maximum current at the conditioningpotentials ranging from −120 mV to −40 mV. V½ or k values were estimatedfrom Boltzmann fits. The affinity of drugs to resting state of Nachannels (K_(resting) or K_(r)) was assessed by 30 msec test pulse froma negative holding potential of ?120 mV, where virtually all channelsare in the resting state. K_(r) value was calculated by a conventional1:1 binding model:

K _(resting)(K _(r))={[drug]Imax,drug/(Imax,control−Imax,drug)}

where K_(resting) (=K_(r)) is a dissociation constant for the restingstate and [drug] is compound concentration. I_(max), control andI_(max), drug are peak currents in the absence and presence of compound,respectively.The affinity of drug to inactivated state of Na channels (K_(inact) orK_(i)) was estimated from the shift of the availability curve bycompound. Interaction of the compound with the channel on inactivatedstate was evaluated by the following equation:

K _(inact)(K _(i))={[drug]/((1+[drug]/K _(r))*exp(−ΔV/k)−1)}  [Math.2]

where K_(inact) (=K_(i)) is a dissociation constant for the inactivatedstate. ΔV is the compound-induced voltage shift of half maximal voltageof Boltzmann curve and k is the slope factor on presence of compound.

The compounds of the examples were tested in the above-described assay.The results are as follows:

All examples of the invention have an IC₅₀=<6 microM in the bothNa_(V1.3) and Na_(V1.7) FRET Assays. Especially example 2, 5, 17, 18,21, 25, 29, 30, 31, 35, 37, 39, 40, 41, 43, 47, 49, 50, 54, 62, 63, 65,66, 68, and 69 of the invention have an IC₅₀=<0.5 microM in both ofthem.

1. A compound of formula (I):

wherein: R¹ is independently selected from the group consisting of: (1)hydrogen, (2) halogen, (3) hydroxy, (4) —O_(p)—C₁₋₆ alkyl, where thealkyl is unsubstituted or substituted with one or more substituentsselected from R⁵, (5) —O_(p)—C₃₋₈ cycloalkyl, where the cycloalkyl isunsubstituted or substituted with one or more substituents selected fromR⁵, (6) C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substitutedwith one or more substituents selected from R⁵, (7) —(C═O)—NR⁶R⁷, (8)—NR⁶R⁷, (9) —S(O)₂—NR⁶R⁷, (10) —NR⁶—S(O)₂R⁷, (11) —S(O)_(r)—R⁸, where ris 0, 1 or 2 and where R⁸ is selected from the definitions of R⁶ and R⁷,(12) —CO₂H, and (13) —CN; where p is 0 or 1 (wherein if p is 0, achemical bond is present in the place of O_(p)); n is 1, 2, or 3; when nis two or more than two, R¹ may be same or different; R² is selectedfrom the group consisting of: (1) hydrogen, (2) C₁₋₆ alkyl, which isunsubstituted or substituted with one or more substituents selected fromR⁵, (3) C₃₋₈ cycloalkyl which is unsubstituted or substituted with oneor more substituents selected from R⁵, (4) phenyl, which isunsubstituted or substituted with one or more substituents selected fromR⁵, and (5) heterocycle, which is unsubstituted or substituted with oneor more substituents selected from R⁵; R³ is selected from the groupconsisting of: (1) —C₀₋₃ alkyl-O_(p)—C₀₋₃ alkyl-cycloalkyl which isunsubstituted or substituted with one or more substituents selected fromR⁵, (2) —C₀₋₃ alkyl-O_(p)—C₀₋₃ alkyl-phenyl, which is unsubstituted orsubstituted with one or more substituents selected from R⁵, and (3)—C₀₋₃ alkyl-O_(p)—C₀₋₃ alkyl-heterocycle, which is unsubstituted orsubstituted with one or more substituents selected from R⁵; where p is 0or 1, (wherein if p is 0, a chemical bond is present in the place ofO_(p)); R⁴ is selected from the group consisting of: (1) hydrogen, (2)C₁₋₆ alkyl, and (3) hydroxy; m is 1, 2, or 3; when m is two or more thantwo, R⁴ may be same or different; R⁴ may form the bond with any ofcarbon atom on the cyclic amine ring; k is 0 or 1; Y is oxygen atom orcarbon atom; R⁵ is selected from the group consisting of: (1) halogen,(2) hydroxy, (3) —(C═O)_(q)—O_(r)—C₁₋₆ alkyl, where the alkyl isunsubstituted or substituted with one or more substituents selected fromR⁹, (4) —O_(p)—(C₁₋₃)perfluoroalkyl, (5) —(C═O)_(q)—O_(r)—C₃₋₈cycloalkyl, where the cycloalkyl is unsubstituted or substituted withone or more substituents selected from R⁹, (6)—(C═O)_(q)—O_(r)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R⁹, (7)—(C═O)_(q)—O_(r)— phenyl or —(C═O)_(q)—O_(r)-napthyl, where the phenylor napthyl is unsubstituted or substituted with one or more substituentsselected from R⁹, (8) —(C═O)_(q)—O_(r)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R⁹, (9) —(C═O)—NR⁶R⁷, (10) —NR⁶R⁷, (11)—S(O)₂—NR⁶R⁷, (12) —S(O)_(t)—R⁸, where t is 0, 1 or 2, (13) —CO₂H, (14)—CN, and (15) —NO₂; where p is 0 or 1, (wherein if p is 0, a chemicalbond is present in the place of O_(p)) and where q is 0 or 1 and r is 0or 1 (wherein if q is 0 or r is 0, a bond is present in the place of(C═O)_(q) or O_(r), and wherein if q is 0 and r is 0, a single bond ispresent in the place of (C═O)_(q)—O_(r)); R⁶ and R⁷ are independentlyselected from the group consisting of: (1) hydrogen, (2) C₁₋₆ alkyl,which is unsubstituted or substituted with R⁵, (3) C₃₋₆ alkenyl, whichis unsubstituted or substituted with R⁵, (4) C₃₋₈ cycloalkyl which isunsubstituted or substituted with R⁵, (5) phenyl, which is unsubstitutedor substituted with R⁵, and (6) heterocycle, which is unsubstituted orsubstituted with R⁵, or R⁶ and R⁷ taken together with the nitrogen atomto which they are attached form a 3 to 8 membered ring, where the ringmay contain one to four heteroatom independently selected from nitrogen,oxygen, and sulfur; where the ring may be saturated or partiallysaturated or unsaturated; which is unsubstituted or substituted one ormore substituents selected from R⁵; R⁸ is selected from the definitionsof R⁶ and R⁷; R⁹ is selected from the group consisting of: (1) hydroxy,(2) halogen, (3) C₁₋₆ alkyl, (4) —C₃₋₈ cycloalkyl, (5) —O—C₁₋₆ alkyl,(6) —O(C═O)—C₁₋₆ alkyl, (7) —NH—C₁₋₆ alkyl, (8) phenyl, (9) heterocycle,(10) —CO₂H, and (11) —CN; or a pharmaceutically acceptable salt thereof.2. The compound as claimed in claim 1 wherein R¹ is independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)hydroxy, (4) —O_(p)—C₁₋₆ alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R⁵, and (5)—O_(p)—C₃₋₈ cycloalkyl, where the cycloalkyl is unsubstituted orsubstituted with one or more substituents selected from R⁵; where p is 0or 1 (wherein if p is 0, a chemical bond is present in the place ofO_(p)); n is 1, 2, or 3; when n is two or more than two, R¹ may be sameor different; R³ is 3 to 8 membered ring where the ring may contain oneto four heteroatom independently selected from nitrogen, oxygen, andsulfur; where the ring may be saturated or unsaturated; and where thering is optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of: (1) hydroxy, (2) halogen, (3)C₁₋₆ alkyl, which is unsubstituted or substituted with one or moresubstituents selected from R⁵, (4) C₃₋₈ cycloalkyl, which isunsubstituted or substituted with one or more substituents selected fromR⁵, (5) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with one ormore substituents selected from R⁵, and (6) —O—C₃₋₈ cycloalkyl, which isunsubstituted or substituted with one or more substituents selected fromR⁵; R⁵ is selected from the group consisting of: (1) halogen, (2)hydroxy, (3) —(C═O)_(q)-Or-C₁₋₆ alkyl, where the alkyl is unsubstitutedor substituted with one or more substituents selected from R⁹,(4)-Op-(C₁₋₃)perfluoroalkyl, (5) —(C═O)_(q)-Or-C₃₋₈ cycloalkyl, wherethe cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R⁹, (6) —(C═O)_(q)-Or-phenyl, where thephenyl is unsubstituted or substituted with one or more substituentsselected from R⁹, (7) —(C═O)_(q)-Or-heterocycle, where the heterocycleis unsubstituted or substituted with one or more substituents selectedfrom R9, (8) —(C═O)—NR6R7, (9) —NR6R7, (10) —S(O)₂—NR⁶R⁷, and (11)—S(O)_(t)—R⁸, where t is 0, 1 or 2; where p is 0 or 1, (wherein if p is0, a chemical bond is present in the place of Op) and where q is 0 or 1and r is 0 or 1 (wherein if q is 0 or r is 0, a bond is present in theplace of (C═O)_(q) or O_(r), and wherein if q is 0 and r is 0, a singlebond is present in the place of (C═O)_(q)—O_(r)); R⁹ is selected fromthe group consisting of: (1) hydroxy, (2) halogen, (3) C₁₋₆ alkyl, (4)—C₃₋₈ cycloalkyl, (5) —O—C₁₋₆ alkyl, (6) —O(C═O)—C₁₋₆ alkyl, (7)—NH—C₁₋₆ alkyl, (8) phenyl, and (9) heterocycle; or a pharmaceuticallyacceptable salt thereof.
 3. The compound as claimed in claim 1, which isselected from:3-(((S)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(4-(trifluoromethoxy)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(4-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(3-chloro-2-fluorobenzoyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(2-(4-(trifluoromethyl)phenyl)acetyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(6-tert-butylnicotinoyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(5-tert-butylisoxazole-3-carbonyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(2-(4-(trifluoromethyl)phenoxy)acetyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(4-(2,2,2-trifluoroethoxy)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,5-chloro-3-(((R)-1-(cis-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,5-chloro-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,5-(trifluoromethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(2-hydroxyethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)—N-(2-methoxyethyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)—N-hydroxycyclohexyl)methyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,Methyl2-(3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamido)acetate,N-(2-methoxyethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-((1-hydroxycyclohexyl)methyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(pyridin-2-ylmethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-benzyl-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-phenyl-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(pyridin-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(4H-1,2,4-triazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N—((R)-2-hydroxy-1-phenylethyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(oxazol-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(tetrahydro-2H-pyran-4-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(5-methylisoxazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(1-methyl-1H-pyrazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(isoxazol-3-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(oxazol-2-yl)-3-(((S)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)-3-((1-(2-(4,4-difluorocyclohexyl)acetyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide,N-(pyrazin-2-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,N-(isoxazol-5-yl)-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)—N-(pyridin-2-ylmethyl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)—N-benzyl-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,(R)—N-(pyridin-2-yl)-3-((1-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-yl)methoxy)picolinamide,3-(((2R,4R)-4-hydroxy-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-N-(isoxazol-3-yl)picolinamide,5-chloro-3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide,5-chloro-3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexanyl)methoxy)picolinamide,3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)picolinamide,N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide,N-(tetrahydro-2H-pyran-4-yl)-3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinamide,N-((tetrahydro-2H-pyran-4-yl)methyl)-3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamideandN-(tetrahydro-2H-pyran-4-yl)-3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinamide.4. A pharmaceutical composition comprising the compound or thepharmaceutically acceptable salt thereof, as claimed in claim 1, and apharmaceutically acceptable carrier.
 5. A pharmaceutical composition asclaimed in claim 4, further comprising another pharmacologically activeagent.
 6. A method for the treatment of a condition or disorder in whichTTX-S channel blockers are involved, in a mammalian subject, including ahuman, which comprises administering to a mammal in need of suchtreatment a therapeutically effective amount of the compound or thepharmaceutically acceptable salt thereof, as claimed in claim
 1. 7. Themethod as claimed in claim 6, wherein said condition or disorder isselected from the group consisting of: pain, acute pain, chronic pain,neuropathic pain, inflammatory pain, visceral pain, nociceptive pain,multiple sclerosis, neurodegenerative disorder, irritable bowelsyndrome, osteoarthritis, rheumatoid arthritis, neuropathologicaldisorders, functional bowel disorders, inflammatory bowel diseases, painassociated with dysmenorrhea, pelvic pain, cystitis, pancreatitis,migraine, cluster and tension headaches, diabetic neuropathy, peripheralneuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy orepileptic conditions, bipolar depression, tachyarrhythmias, mooddisorder, bipolar disorder, psychiatric disorders such as anxiety anddepression, myotonia, arrhythmia, movement disorders, neuroendocrinedisorders, ataxia, incontinence, visceral pain, trigeminal neuralgia,herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicularpain, sciatica, back pain, head or neck pain, severe or intractablepain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizuredisorder and causalgia; and combinations thereof. 8-10. (canceled)